1. health and fitness
2. disease
3. asthma

New Therapies in Asthma
By Suzanne G. Bollmeier, Pharm.D., BCPS, AE-C
Reviewed by Wendy Brown, Pharm.D., MPAS, PA-C, AE-C; Autumn L. Stewart, Pharm.D., BCACP;
and Nancy S. Yunker, Pharm.D., BCPS
Learning Objectives
health care system. Asthma can influence quality of life by
causing missed school or work days, medical expenses, and
premature death. A growing body of knowledge about the
pathophysiology, the hygiene hypothesis, and the environmental factors leading to the development of asthma has
enabled researchers to better target future therapies.
Ambulatory care pharmacists have a unique opportunity to serve patients with asthma. The National
Asthma Education and Prevention Program Expert Panel
Report 3 (EPR-3) guidelines call for asthma self-management education to be integrated into all aspects of
care (EPR-3 2007). With extensive education on asthma
pathophysiology, therapeutics, and inhalation/device
technique, the pharmacist is an integral part of the health
care team providing education and helping maintain
asthma control.
The impact of pharmacist-provided services for individuals with respiratory disorders has been documented.
Pharmacist interventions lead to decreased symptoms
and improvement in asthma severity (Benavides 2009).
Pharmacist-driven medication therapy management
1. Evaluate interventions based on the etiologies, status,
and control of asthma.
2. Develop and justify optimal therapeutic regimens
based on the underlying pathophysiology of asthma
and current evidence.
3. Devise an asthma education care plan for a patient or
family member(s).
4. Demonstrate an understanding of pharmacogenomic
testing and how results influence treatment decisions
in patients with asthma
5. Demonstrate an understanding of emerging therapies in the treatment of asthma and judge when they
would be applicable in patient care
6. Display insight into technological advances in
asthma care and recommend them to patients when
appropriate.
Introduction
Asthma is an episodic yet chronic disease that places a
heavy economic burden on patients, their families, and the
Baseline Knowledge Statements
Readers of this chapter are presumed to be familiar with the following:
• On the basis of a patient’s specific medical history, interview, and objective findings, ascertaining asthma severity and current level of control, as well as preferred and alternative treatments, as established by National Asthma
Education and Prevention Program EPR-3.
• Delineating the differences in inhaled steroid potency as low, medium, and high as established by EPR-3.
• Establishing approaches to address patient adherence (e.g., medication possession ratio), inhaler techniques (e.g.,
In-Check Dial, 2Tone Trainer), basic environmental control, and comorbid conditions before stepping up treatment.
• Identifying optimal step-down treatment in well-controlled patients.
Additional Readings
The following free resources are available for readers wishing additional background information on this topic.
• National Asthma Education and Prevention Program Expert Panel Report 3.
• Global Initiative for Asthma Treatment Guidelines.
• QualityMetric. Asthma Control Test.
• Merck. Asthma Therapy Assessment Questionnaire.
ACSAP 2013 • Pulmonary and Preventive Care
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New Therapies in Asthma
children (13.6%) will receive a diagnosis of asthma during their lifetimes. The prevalence of asthma has risen
by 14.8% in less than 10 years (2001 to 2010) (Asthma
Impact on the Nation 2011).
Abbreviations in This Chapter
ACO
ADRB2 Arg16
EPR-3 FEV1
Accountable care organization
β2-Adrenergic receptor
ADRB2 polymorphism
Expert Panel Report 3
Forced expiratory volume in 1
second
FVC
Forced vital capacity
HFAhydrofluoroalkane
ICS Inhaled corticosteroid
LABA Long-acting β-agonist
NO
Nitric oxide
PEF
Peak expiratory flow
SABA
Short-acting β-agonist
SMART
Single maintenance and reliever
therapy
Th
T-helper (cell)
TLR
Toll-like receptor
Incidence and Economic Impact
The incidence of asthma is disproportionately higher
among children, women, individuals in lower-income
socioeconomic groups, and the African American and
Hispanic populations. The death rate, too, is highest
among those patient groups. Asthma’s economic impact
is alarming: from 2002 to 2007, the annual cost was $56
billion, with direct health care costs of $50.1 billion and
indirect costs of an additional, $5.9 billion. The cost of
asthma is not limited to medical and drug costs; lost productivity is also a major factor. According to the CDC,
59% of children and 33% of adults missed school or work
because of asthma attacks in 2008. Annually, the average number of school days missed was 4, and work days
missed averaged 5.
Pathophysiology
services are also beneficial financially. The Asheville
Project demonstrated that with increased spending
on asthma drugs, a net savings resulted because of less
absenteeism and fewer emergency department (ED) visits and hospitalizations (Bunting 2006). Pharmacists are
uniquely situated within the health care team to care for
patients with asthma. The Affordable Care Act is establishing new models for delivering services to Medicare beneficiaries. An
accountable care organization (ACO) is a network of doctors, hospitals, and other health care suppliers working
together to coordinate and improve the quality of patient
care. In this model, an ACO would be responsible for keeping patients healthy and out of the hospital. This involves a
shift from the traditional fee-for-service structure to payments based on quality metrics and reductions in the total
cost of care (Gold 2011). The ACO must meet quality standards in five areas: (1) patient/caregiver care experience, (2)
care coordination, (3) patient safety, (4) preventive health,
and (5) at-risk population/frail elderly health. Pharmacists
working with providers in both outpatient and inpatient
settings can aid ACOs by supporting initiatives that meet
these standards. For example, improving adherence in the
use of controller drugs and in applying appropriate device
technique can decrease ED visits and hospitalizations for
asthma. Clinical pharmacists in ACOs may also address drugrelated issues by contracting to provide medication therapy
management or medication reconciliation services.
Host Factors
Asthma is a complex compilation of signs and symptoms that are patient specific. The general etiologic factors
that predispose a person to asthma are atopy and exposure
to environmental triggers. Compared with developing
nations, the incidence and prevalence of asthma are much
higher in Western countries because of changes in
lifestyles that include extremely clean household environments and fewer circulating infectious diseases. This
so-called hygiene hypothesis is based on scientific observation that because of lack of exposure to infectious
organisms, the immune system is no longer challenged
adequately in children born in industrialized nations
(Schroder 2008). In this model, the developing immune
system shifts the balance between what would normally
be equal parts of T-helper (Th) cells type 1 and type 2
(Okada 2010). The lack of exposure to bacteria shifts the
immune system toward a Th2 cell–mediated immunity
(Figure 1-1). This shift favors the development of allergic
disorders, including asthma, because Th2 cells produce
interleukins (i.e., IL-4, IL-5, IL-6, and IL-13) that contribute to atopy through immunoglobulin E production.
Environmental Factors
Together with the hygiene hypothesis, the best evidence is that environmental influences can trigger asthma
or predispose a person to asthma. These influences include
exposure to allergens, inhalation of tobacco smoke, the
presence of air pollution, and obesity. Indoor allergens
associated with the development of asthma include mold,
dust mites, animal dander (Gaffin 2009), and cockroaches
(Gao 2011). House dust mites are highly allergenic antigens and cause the highest rates of positive skin-prick
Epidemiology
It is estimated that in the United States, 18.7 million
adults (8.2%) and 7 million children (9.4%) have asthma,
and that 29.1 million adults (12.7%) and 10.1 million
New Therapies in Asthma
2
ACSAP 2013 • Pulmonary and Preventive Care
Suppresses autoimmune responses
CpG in
DNA of
bacteria
T (reg)
TNF-α
Bind to TLR
Presented by dendritic cell
golim
Intracellular signaling
Th17
IL-17
CD4 T cell
Cytokine/chemokine
production
oligonucleotides
TLR
GM-CSF
(INNATE)
Th1
CXCR3
neutrophils
TNF-α
Severe disease
“steroid resistance”
more likely
IL-8
CCR5
golim
IL-12
CRTH2
DP
DP 1
CCR4
CCR8
*enhance mast
cell growth
*↑ mucus
* ↑ BHR
DP
CCR3
Anticytokines
IL-2
IFN-γ
IL-4
CRTH2
antagonist
Activates
macrophage
IL-9, IL-10, IL-13
IL-6
IL-5
GM-CSF
Eosinophil
recruitment
PGD2
DP
DP agonist
IgE
Can cause
Recruits
Binding to DP
rec on PGD2
(ADAPTIVE)
Th2
Promotes infiltration
of inflammatory cells
1) ↑ CAMP
2) smooth muscle relaxation
3) suppresses cell migration
Omalizumab
1) bronchoconstriction
2) vasodilation
3) ↑ cap permeability
4) ↑ mucus
1) Th2
2) eosinophils
3) basophils
Stimulates release of mature
eosinophils from bone marrow
Binds to mast cells
Growth and
differentiation of
Delays eosinophil apoptosis
Neutrophil
Eosinophil
recruitment
golimumab
Mast cells
DP
eosinophils
CRTH2
TNF-α
PgD2
leukotrienes
montelukast
IL-4
Antihistamines
Histamine
IL-10
IL-5
IL-13
LT C4
Figure 1-1. The role of existing and emerging therapies in the inflammatory cascade.
KEY
Dashed line boxes = receptor;
= Antagonist / mechanism of action is blockade of the pathway
= Agonist / mechanism of action is promotion of the pathway
BHR = bronchial hyperresponsiveness, CAMP = cyclic adenosine monophosphate, CCR = chemokine receptor, CD4 = specific type of T immune cell,
CpG = unmethylated sequences of DNA that have immunostimulatory properties, CRTH2 = chemoattractant receptor, CXCR3 = chemokine receptor
CXCR3, DP = PgD2 receptor, DP1 = PgD2 receptor, GM-CSF = granulocyte-macrophage colony-stimulating factor, IFN-γ = interferon gamma, IgE =
immune globulin E, IL = interleukin, LT C4 = leukotriene C4, PgD2 = prostaglandin D2, T (reg) = regulatory T cell, Th = T helper cell; TLR = toll-like
receptor, TNFα = tumor necrosis factor-alpha
Information from Arima M, Fukuda T. Prostaglandin D2 receptors DP and CRTH2 in the pathogenesis of asthma. Curr Mol Med 2008;8:365-75; Arima
M, Fukuda T. Prostaglandin D2 and Th2 inflammation in the pathogenesis of bronchial asthma. Korean J Int Med 2011;26:8-18; Hansbro PM, Kaiko GE,
Foster PS. Cytokine/anti-cytokine therapy—novel treatments for asthma? B J Pharmacol 2011;163:81-95; Pettipher R, Hansel TT, Armer R. Antagonism of
the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases. Nature 2007;6:313-25; and Schuligoi R, Strum E, Luschnig P, et
al. CRTH2 and D-type prostanoid receptor antagonists as novel therapeutic agents for inflammatory diseases. Pharmacology 2010;85:372-82.
ACSAP 2013 • Pulmonary and Preventive Care
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New Therapies in Asthma
testing in atopic patients (Keogh, Parker 2011). Of known
molds, Alternaria provokes symptoms of asthma most routinely (Fernandez 2011). Pets are also allergenic, although
if a child has no family history of allergic diseases, pet
ownership may be protective. The relationship with a pet
is less straightforward in children with family histories of
allergic diseases (Lodge 2011). It is postulated that cockroach allergen consists of a combination of cockroach
bodies, feces, and saliva-containing proteins and proteases that can disrupt the airway epithelium (Gao 2011).
Exposure to tobacco smoke and air pollution are also
linked to the onset of asthma (Flodin 1995). Both active
smoking and exposure to secondhand smoke have long
been known as triggers of asthma symptoms. The onset
of pediatric respiratory illnesses may begin during fetal
development. Exposure to tobacco smoke early in life
diminishes airway function and decreases lung growth
(Stocks 2003). Those reductions cause changes in forced
vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and maximal midexpiratory flow. Maternal
smoking is linked to infant wheezing (Jindal 2004). The
role of air pollution (e.g., nitrogen dioxide, ozone, particulate matter generated by industry and vehicle traffic) in
causing asthma is less clear (Takizawa 2011), although
exposure to high levels of air pollution is a well-known
trigger for exacerbations (Rosenlund 2009) and can also
lead to reduction in lung growth (Gauderman 2004)
brought on by oxidative stress and carbon accumulation
in macrophages (Rosenlund 2009).
Set (HEDIS) is an instrument health plans use to gauge
quality of care of patients (Box 1-1). Better quality of care
of asthma for a particular population (e.g., across members of a health plan) can be assessed by such performance
measures as survey data and administrative (pharmacy)
data (Schatz 2011). The medication ratio measure is the
ratio of controllers to total asthma drugs (controllers plus
rescue inhalers) dispensed in a 12-month period. The relationship between a medication ratio of 0.5 or greater and a
reduced likelihood of subsequent asthma exacerbations has
been established. Also, low scores on three validated questionnaire tools reflect asthma impairment: Asthma Control
Test (ACT) score lower than 16, Asthma Quality of Life
Questionnaire score of 4.7 or lower, and Asthma Impact
Survey score higher than 60) (Schatz 2011). The degree
of impairment is not specified, and it should be noted that
according to EPR-3, the cutoff value for poorly controlled
asthma is an ACT score lower than 19.
Overreliance on quick-acting albuterol can increase the
risk of uncontrolled asthma and asthma fatalities (Spitzer
1992). Other risk factors associated with near-fatal exacerbations are nonadherence and poor access to care (Carroll
2010). By applying these criteria to their own patients,
providers can better focus attention on patients at highest risk. Pharmacists can assist by informing providers of
refill histories and compliance markers and by educating
patients on the importance of adherence, on good device
technique, and on proper use of quick-acting agents.
Prevention of Acute Asthma
Acute asthma episodes or exacerbations are random and
alarming, and they impair quality of life. Patients can prevent exacerbations by adhering to controller drug regimens
and avoiding known triggers. Patients should also be immunized against influenza annually. Those 19 years or older
should also receive pneumococcal polysaccharide vaccine.
Most patients with asthma are poor perceivers of
asthma control. In a recent study, nearly three-fourths
of adolescents rated themselves as having good disease
Obesity and Asthma
Obesity may be a possible cause of asthma. During
2009–2010, more than one-third of U.S. adults and about
17% of children were obese (Ogden 2011). With both
asthma and obesity increasing in prevalence, an association between the two is being explored. Interpreting
the results of asthma and obesity trials can be difficult
because objective measures of both asthma diagnoses and
weight are not uniform. Confounding biases such as diet
and physical activity also vary across studies. Overweight
or obesity is not a risk factor for atopy or eosinophilia,
suggesting that obesity may affect the airway through
mechanisms other than allergic inflammation, such as
increased oxidative stress, airways narrowed by chest
restriction, and obesity-related comorbidities such as
obstructive sleep apnea and gastroesophageal reflux disease (Lang 2012; Lugogo 2010).
Box 1-1. HEDIS Measures for Identifying High-Risk
Patients with Asthma
A patient is considered at high risk if any of the
following criteria were met in the past year:
• ≥ 1 emergency department visit for asthma
• ≥ 1 hospitalization for asthma
• Use of ≥4 asthma medication prescriptions
• ≥ 4 ambulatory visits for asthma with ≥2 asthma
drug prescriptions
Screening and Prevention
High-risk Population Identification and Management
Asthma is the most common pediatric respiratory disorder that can continue into adulthood. Identification of
patients at high risk of exacerbations can improve asthma
outcomes and decrease costs by leading to improved asthma
care. The Healthcare Effectiveness Data and Information
New Therapies in Asthma
HEDIS = Healthcare Effectiveness Data and Information Set.
Information from Bennett AV, Lozano P, Richardson LP, et al.
Identifying high-risk asthma with utilization data: a revised
HEDIS definition. Am J Manag Care 2008;150-6. 4:4
4
ACSAP 2013 • Pulmonary and Preventive Care
control. However, when evidence-based criteria were
applied, only 8% actually had good control (Britto 2011).
The way that patients with asthma describe symptoms—
especially dyspnea—is consistent from age 8 years though
adulthood (Harver 2011). Because symptom descriptions are to a large extent universal, pharmacists can help
patients develop self-efficacy, especially in recognizing the
signs and symptoms of poor control (Box 1-2) and knowing when to seek medical care.
Current guidelines recommend that a patient have a selfmanagement asthma action plan in place to direct both
controller and acute symptom treatment. Such plans may
include how to adjust reliever and controller drugs, as well
as how to minimize and control environmental triggers.
Action plans empower patients to handle acute situations
while minimizing panic and stressing adherence. As of
2010, all 50 of the United States protect a student’s right
to carry and self-administer asthma drugs while at school.
State legislative requirements are available online, and the
CDC Web site is a resource for action plans.
and the exclusion of other causes (EPR-3 2007). The
guidelines recommend clinicians perform a physical
examination and obtain a medical history. Spirometry
should be performed in all patients older than 5 years
to assess for airway obstruction and reversibility.
Reversibility is defined as a change in baseline FEV1
of greater than 200 mL and 12% after inhalation of a
short-acting β-agonist (EPR-3 2007). Because histamine and methacholine act directly on smooth muscle
cells to cause bronchoconstriction and airway hyperresponsiveness (Sverrild 2010), a bronchial provocation
test using histamine or methacholine may be necessary
to definitively rule out asthma in patients with normal
spirometry who remain symptomatic (Sverrild 2010).
Additional tests may be necessary to exclude other diagnoses such as gastroesophageal reflux disease, vocal cord
dysfunction, a foreign object in the airway, or a bacterial
or viral infection.
The prognosis of asthma is challenging because no
absolute indicators are available. However, the persistence
of childhood asthma into adulthood can be predicted by
the presence of available risk factors (Table 1-1).
Evidence for Prevention with Drug Therapy
To limit the risk of acute exacerbations, providers should urge patients to adhere to controller drugs.
Providers should also recommend inhaled corticosteroids
(ICSs) over alternatives such as montelukast, theophylline, and nebulized cromolyn. Patients should be treated
in a stepwise manner according to their asthma stage at
diagnosis or level of control. More information is available
in the EPR-3 guidelines.
Treatment Goals
Patients, in company with their clinicians, should
be encouraged to identify goals of treatment. Engaging
a patient in a mutually agreed-upon treatment plan
increases patient commitment to both short- and longterm treatment goals. General goals of treatment are
to prevent acute and chronic symptoms, maintain normal pulmonary function, minimize adverse drug effects,
maintain normal activity levels, and meet the patient and
family expectations of care (EPR-3 2007). Clinicians
should identify any culture-related beliefs regarding goals
of therapy, use open-ended questioning techniques, and
involve the family in the decision-making process. More
information about the use of motivational interviewing is
available online.
Diagnosis and Prognosis
EPR-3 Diagnostic Criteria
Criteria for diagnosis of asthma include the presence of episodic signs and reversible airflow obstruction
Box 1-2. Signs and Symptoms Indicating Poor
Asthma Control
• Shortness of breath or wheezing > 2 days/week
• Nighttime awakenings > 1 day/week
• Some limitation in normal activity
• Use of quick-acting agent > 2 days/week
• FEV1 or peak flow 60% to 80% predicted or
personal best
• Score of > 1 on ATAQ , ≥ 1.5 on ACQ , or < 19
on ACT QOL questionnaires
Quality Patient Care
Trigger Avoidance
Patients should learn to recognize their own asthma
symptom triggers. The most common triggers are viral
or bacterial infections, allergens such as animal dander
or pollen, and exposure to tobacco smoke. Others triggers are high levels of air pollution, occupational exposure
to chemicals, drugs such as β-blockers, exercising, and
food preservatives. If triggers are identified and aversion
is discussed, the patient is more likely to avoid the triggers (Rank 2010). Although trigger avoidance usually is
discussed during or after an asthma exacerbation, opportunities should be captured in the outpatient setting as
well.
ACQ = Asthma Control Questionnaire, ACT = Asthma Control
Test, ATAQ = Asthma Therapy Assessment Questionnaire, QOL
= quality of life
Information from National Heart, Blood, and Lung Institute.
National Asthma Education and Prevention Program. Expert
Panel Report 3. Guidelines for the diagnosis and management
of asthma. 2007.
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New Therapies in Asthma
Table 1-1. Risk Factors for Persistent Asthma
Children younger than 3 years who, in the past year, have experienced four or more episodes of wheezing that lasted more
than 1 day and affected sleep are more likely to have persistent asthma after the age of 5 years if they also have:
One of the following:
Parental history of asthma
Diagnosed atopic dermatitis
Evidence of sensitization to aeroallergens
Or two of the following:
Evidence of sensitization to foods
≥4% peripheral blood eosinophilia
Wheezing apart from colds
Information from National Heart, Blood, and Lung Institute. National Asthma Education and Prevention Program. Expert Panel Report 3.
Guidelines for the diagnosis and management of asthma. 2007.
Environmental Control
Similar to trigger avoidance, controlling the patient’s
environment could lead to better health outcomes.
Reducing environmental triggers in urban-living children can decrease reliance on the emergency department,
shorten the length of hospital stays, and reduce the number
of sick visits to clinicians because of asthma (BryantStephens 2008). Pharmacists, too, can educate patients to
avoid exercise during poor air quality days, to empty trash
receptacles often to avoid the presence of cockroaches,
and to use mattress encasings that limit dust mite exposure. Pharmacists are well positioned—and should be
prepared—to discuss smoking cessation techniques and
pharmacotherapies in patients with asthma and their
household contacts and how to control exercise-induced
bronchoconstriction. More information is available at the
Environmental Protection Agency’s Web site. Pharmacists
can also refer patients with questions related to exerciseinduced bronchoconstriction to the American Academy of
Allergy Asthma & Immunology Web site.
The genetic polymorphism with the most data and
interest is the β2-adrenergic receptor (ADRB2), which
is linked to bronchodilator response (Lima 2009). The
ADRB2 gene is located on chromosome 5q31.32. Two
mutations on this gene result in amino acid exchanges at
the receptor (arginine 16 to glycine [Arg16 Gly] and glutamine 27 to glutamic acid [Gln 27 Glu]). The changes in
those two positions decrease agonist binding and cause
down-regulation of the receptor (Finkelstein 2009).
Those polymorphisms may also lead to decreased pulmonary function, cause poor bronchodilator responsiveness,
and contribute to as much as 60% of variations in response
to albuterol (Hizawa 2011). Table 1-2 describes the distribution of β2-adrenergic receptor alleles in the general
population.
Thr-Ile164 is a rare polymorphism (allelic frequency
of only 3% in whites) that can alter agonist binding properties and adenylyl cyclase activation. Patients with this
polymorphism may experience as much as a 50% decrease
in the duration of action of salmeterol because of altered
binding to the receptor (Hall 2007).
Although genetic testing is not yet commonplace, pharmacists may be called upon in the future to help patients
and prescribers understand genetically driven therapies.
Home test kits for the Arg16 polymorphism are available over the Internet; however, the U.S. Food and Drug
Administration (FDA) has not approved the labeled use of
such kits. More information is still needed to fully understand the role of the ADRB2 gene, polymorphisms, and
the role the ADRB2 gene plays in β-agonist responsiveness
and in asthma itself. Pharmacists should feel confident
about continuing to recommend LABAs plus ICSs for
patients with moderate to severe persistent asthma. If a
genotype is known, however, tailored therapy is appropriate (Figure 1-2).
Recent Outcomes Evidence
Pharmacogenomic Testing
The successful mapping of the human genome and
advances in pharmacogenomics can help identify genetic
markers that influence how humans respond to drugs.
In the future, predictive medicine will be commonplace. New tools for assessment and targeted drugs with
improved efficacy and limited adverse effects will also
become available. To date, pharmacogenomics research
in asthma focuses primarily on the use of and response to
short-acting β-agonists (SABAs) (Blakey 2011). Albuterol
is the most commonly prescribed asthma drug worldwide
(Corvol 2008), and determining which patients respond
to this agent can potentially improve outcomes. Similarly,
excessive SABA use and the use of long-acting β-agonists
(LABAs) as monotherapy have been linked to asthma
mortality; it is unknown whether this association is caused
by genetic variations or the result of uncontrolled inflammation (EPR-3 2007).
New Therapies in Asthma
Pharmacogenomic Data
SABA Data
Most pharmacogenomic studies in patients with
asthma focus on the Arg16 polymorphism. Data suggest
that patients who are homozygous for Arg16 have a greater
initial bronchodilator response to inhaled β2-agonists;
6
ACSAP 2013 • Pulmonary and Preventive Care
however, with repeated exposure, these patients demonstrate down-regulation, and a reduced response occurs
(Hall 2007). Patients homozygous for Arg16 may be
protected against this lack of response to LABA agents
by using an ICS (Hall 2007). The consequences of the
ADRB2 gene on β-agonist response may be linked to
the duration of therapy. Patients who are homozygous
for Arg16 and treated with regular SABAs exhibit lower
peak expiratory flow (PEF) than Gly16 homozygous (Gly/
Gly) patients. Patients homozygous for Arg16 and mild
persistent asthma derive benefit from using ipratropium
as a rescue drug. Such patients had worsening symptom
scores, reduced lung function, and increased rescue drug
use when using salbutamol (albuterol) (Israel 2004).
Contrary to those findings, another study found that
albuterol maximally increased FEV1 to a greater extent in
patients homozygous for Arg16 compared with a cohort
of Gly16 carriers (18% vs. 4.9%, p<0.03) (Lima 1999).
To further complicate the debate, a later meta-analysis of
trials included children with Arg16 Gly and Gln27 Glu
polymorphisms. In children with asthma and the homozygous Arg16 genotype, an association between a favorable
therapeutic response to inhaled SABA (odds ratio [OR]
1.77; 95% confidence interval [CI] 1.01–3.1) was reported
compared with Arg16/Gly16 (heterozygous Arg16) or
homozygous Gly16 genotypes. The beneficial effect of
homozygous Arg16 was most pronounced in African
American children (OR 3.54; 95% CI 1.37–9.13). No association was found between polymorphisms at position 27
of ADRB2 and response in children (Finkelstein 2009).
cohort included patients who were homozygous to either
Arg16 or Gly16. The mean morning PEF in the homozygous Arg16 subjects was 21.4 L/minute greater in the
salmeterol group than in the placebo group (p<0.0001).
Similarly, patients with homozygous Gly16 had morning
PEFs that were 21.5 L/minute greater when assigned to
salmeterol versus placebo (p<0.0001). Neither genotype
had a specific advantage for ipratropium versus salbutamol. The authors concluded that homozygous Arg16 and
homozygous Gly16 patients with asthma had similar—
and substantial—improvements in airway function when
salmeterol was added to ICS therapy (Wechsler 2009).
That same year, another group studied the effect of
ADRB2 polymorphism on asthma control in Korean
patients receiving combination therapy. The cohort
included patients with Arg/Arg, Arg/Gly, and Gly/Gly
polymorphisms. During the 24-week active treatment
phase, patients were started on budesonide 160 mcg and
formoterol 4.5 mcg twice daily. After 8 weeks, the patients
with the Arg/Arg genotype had significantly higher FEV1
and maximal midexpiratory flow than did those with the
Arg/Gly or Gly/Gly genotype (p<0.05). After 24 weeks,
the patients with the Arg/Arg genotype had a significantly higher quality of life than the Arg/Gly or Gly/Gly
group (p<0.05). Such results demonstrate that combination ICSs and LABAs as maintenance therapy would have
more benefit for patients with the Arg/Arg genotype than
patients with the other genotypes. This is not consistent
with previous studies in white subjects (Kim 2009).
Patient response to corticosteroids also may be linked
to pharmacogenomics. The anti-inflammatory properties of corticosteroids are enhanced by ADRB2 activation.
That theoretical mechanism explains the synergy seen
between ADRB2 and glucocorticoid receptor activation.
Binding to the ADRB2 receptor also leads to desensitization and down-regulation through a negative feedback
loop. The clinical manifestation is tachyphylaxis with
ADRB2-agonist therapy (Chung 2011). In vitro studies
show glucocorticosteroids prevent and reverse the desensitization caused by chronic exposure to β-agonists (Tse
2011). Greater down-regulation of receptors was reported
in those homozygous for the Gly16 genotype than in those
homozygous for Arg16. That down-regulation of receptors
in patients with Glu27 genotype is less compared with
those with the Gln27 genotype (Chung 2011), thereby
helping predict possible tachyphylaxis with continued
SABA therapy (see Figure 1-2).
LABA Data To determine the effect of long-acting β-agonists in
patients with ADRB2 polymorphisms, the Long-Acting
Beta Agonist Response by Genotype (LARGE) trial studied the effect of β2-adrenergic receptor polymorphism
on the response to long-acting β2-agonist in asthma. The
Table 1-2. Distribution of β2-Adrenergic Receptor
Alleles in the General Population
Allele
Description
Proportion
Arg16/Arg16
Homozygous Arg16
15%
Arg16/Gly16
Heterozygous Arg 16
38%
Gly16/Gly16
Homozygous Gly16
45%
Gly27/Gly27
Homozygous Gly27
26%
Gln27/Glu27
Heterozygous Gln27
49%
Glu27/Glu27
Homozygous Glu27
22%
Pharmacogenomic Summary
Pharmacists may be asked to help patients understand
genetically driven therapies. Genetic testing is increasingly available. A home test kit, currently on the market
for around $300, uses the DNA obtained from a cheek
swab sample to assess for the Arg/Arg polymorphism in
the ADRB2 gene. Such information may benefit patients
by allowing treatment plans to be based on evidence
Information from Lima JJ, Thomason DB, Mohamed MHN, et
al. Impact of genetic polymorphisms of the β2-adrenergic receptor on albuterol bronchodilator pharmacodynamics. Clin Pharm
Ther 1999;65:519-25.
ACSAP 2013 • Pulmonary and Preventive Care
7
New Therapies in Asthma
ADULT PATIENT
Severe persistent asthma
Patient characteristics (before
treatment):
• Symptoms throughout day
• Nightly awakenings
• SABA use throughout day
• Extremely limited activity level
• FEV1< 60% predicted
Very poorly controlled asthma
despite therapy
Patient characteristics:
• Symptoms throughout the day
• Nighttime awakenings ≥4 times/week
• Extremely limited activity level
• SABA use throughout the day
• FEV1 < 60% predicted or personal best
• ATAQ questionnaire score 3-4
• ACT score ≤ 15
OR
Patient is symptomatic despite current
medications including:
High dose ICS
• Beclometh > 480 mcg/day
• Budesonide > 1200 mcg/day
• Flunisolide > 2000 mcg/day
• Fluticasone MDI > 440 mcg/day
•
DPI > 500 mcg/day
• Mometasone > 400 mcg/day
• Ciclesonide ≥ 320 mcg BID
LABA
• +/- oral glucocorticosteroid
Patient:
• Is adherent
• Displays proper device technique
• Limited environmental triggers
• Co-morbid conditions (GERD,
allergic rhinitis) are controlled
Bronchial Thermoplasty
Are the following tests available?
Yes
No
Yes
Genotyping
16Arg/Arg
Arg16/Gly
27 Glu/Glu
Yes
FeNO
Induced sputum
16 Gly/Gly
Predominant WBC found
27 Gln/Gln
Eosinophils
> 14 parts/billion
Neutrophils
LABA
ICS
LABA
SABA
LABA
ICS
Patient remains symptomatic
or uncontrolled?
Add tiotropium 18 mcg once daily
OR
Decrease dosage of high-dose ICS by half and add tiotropium 18 mcg once daily
Nonresponder
8-12 week trial
Discontinue
tiotropium
Respond
Continue
tiotropium
Figure 1-2. Decision tree for the patient with asthma.
FEV = forced expiratory volume; FEV1 = forced expiratory volume in 1 second; ICS = inhaled corticosteroid; LABA = long-acting
β-agonist; SABA = short-acting β-agonist.
Information from Bateman ED, Kornmann O, Schmidt P, et al. Tiotropium is noninferior to salmeterol in maintaining improved lung
function in β16-ARG/ARG patients with asthma. J Allergy Clin Immunol 2011;128:315-22; Fardon T, Haggart K, Lee DKC, et al. A proof
of concept study to evaluate stepping down the dose of fluticasone in combination with salmeterol and tiotropium in severe persistent
asthma. Respir Med 2007;101:1218-29; Iwamoto H, Yokoyama A, Shiota N., et al. Tiotropium bromide is effective for severe asthma with
noneosinophiic phenotype. Eur Respir J 2008;31:1379-82; Kerstjens HA, Disse B, Schroder-Babo W, et al. Tiotropium improves lung
function in patients with severe uncontrolled asthma: a randomized controlled trial. J All Clin Immunol 2011 128:308-14; Kerstjens
HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 2012;367:1198207; Park HW, Yang MS, Park CS, et al. Additive role of tiotropium in severe asthmatics and Arg16Gly in ADRB2 as a potential marker to
predict response. Allergy 2009;64:778-83; and Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step up therapy for adults
with uncontrolled asthma. N Engl J Med 2010;363:1715-26.
New Therapies in Asthma
8
ACSAP 2013 • Pulmonary and Preventive Care
regarding their genotype. More information is still
needed to fully understand the role of the ADRB2 gene,
of polymorphisms, and of the gene’s role in both β-agonist
responsiveness and asthma itself.
2008). African American and Asian populations have an
increased prevalence of the Arg16 genotype, and the use
of alternative controllers and rescue inhalers other than
LABAs and SABAs may be appropriate. One study found
that tiotropium had a prolonged bronchodilating effect
and provided protection against inhaled methacholine in
patients with asthma (O’Connor 1996). In a later study,
asthma patients received high-dose fluticasone that was
stepped down to a one-half dose with either salmeterol
and placebo or salmeterol and tiotropium. The authors
found that the triple-drug therapy (ICS dose decreased by
half plus salmeterol and tiotropium) resulted in a statistically significant mean improvement in FEV1 and FVC
(Fardon 2007) (Table 1-3).
In 2008, another team investigated the efficacy of
tiotropium in 17 patients with severe asthma taking 800–
1600 mcg daily of budesonide or equivalent. The authors
found that the more eosinophils in the sputum, the less
likely it was that the patient would respond to tiotropium. The opposite was true for patients with a majority
of sputum neutrophils. Patients on medium to high doses
of ICSs with noneosinophilic sputum profiles had better
responses to tiotropium, which is not surprising given the
value of tiotropium in patients with chronic obstructive
pulmonary disease when neutrophilic inflammation is
widespread (Iwamoto 2008).
Role of Tiotropium for Asthma
The use of anticholinergic drugs in patients with
asthma has been relegated primarily to the acute setting.
The use of ipratropium results in fewer hospitalizations if
given in combination with a SABA to patients experiencing exacerbations in the emergency department (EPR-3
2007). The use of anticholinergic drugs in asthma is fitting. Acetylcholine, a parasympathetic neurotransmitter,
stimulates muscarinic receptors; this results in smooth
muscle contraction, release of mucus from submucosal glands, airway inflammation, and airway remodeling
(Gosens 2006). Cholinergic tone can also become exaggerated when stimulated by inflammatory mediators
such as histamine, prostaglandins, and bradykinin. Other
mechanisms that may increase cholinergic tone in airways
include increased release of acetylcholine from cholinergic
nerve terminals, abnormal muscarinic receptor expression (increase in M3, decrease in M2), and a decrease in
neuromodulators such as nitric oxide and intestinal peptide (Kanazawa 2008).
As previously mentioned, patients who are homozygous for Arg16 may not respond to β2-agonists (Metzger
Table 1-3. Stepping Down Fluticasone in Severe Persistent Asthma
Mean peak flow rates 4 weeks after treatment
Treatment
Fluticasone 1000 mcg/day
Fluticasone 500 mcg/day
Salmeterol 50 mcg twice daily
Placebo
Fluticasone 500 mcg/day
Salmeterol 50 mcg twice daily
Tiotropium 18 mcg daily
Morning PEF
-
41.5 (14.4-68.6) L/minute (p<0.01)
55.3 (31.97-78.7) L/min
(p<0.01)
Evening PEF
Mean lung function values (SEM)
Treatment
Fluticasone 1000 mcg/day
37 (12-63) L/minute
44 (26-62) L/minute
Fluticasone 500 mcg/day
Salmeterol 50 mcg twice daily
Placebo
FEV1 (L)
FEV1 (%)
FVC (L)
FVC (%)
1.73 (0.12)
60 (3.1)
2.57 (0.19)
72 (3.1)
Fluticasone 500 mcg/day
Salmeterol 50 mcg twice
daily
Tiotropium 18 mcg daily
1.79 (0.12)a
62 (2.9)a
2.68 (0.19)a
1.62 (0.14)
55 (2.9)
2.44 (0.2)
68 (3.6)
75 (2.8)a
Statistically significant.
FEV1 = forced expiratory volume at 1 second, FVC = forced vital capacity, PEF = peak expiratory flow
Information from Fardon T, Haggart K, Lee DKC, et al. A proof of concept study to evaluate stepping down the dose of fluticasone in
combination with salmeterol and tiotropium in severe persistent asthma. Respir Med 2007;101:1218-29.
a
ACSAP 2013 • Pulmonary and Preventive Care
9
New Therapies in Asthma
The best-known trial on the use of tiotropium in
patients with asthma was conducted for the Asthma
Clinical Research Network and sponsored by the National
Heart, Lung, and Blood Institute. The study evaluated
whether adding tiotropium to an ICS would be superior to
doubling the dose of the ICS. The three-way, double-blind,
triple-dummy, crossover-designed trial enrolled patients
with mild asthma not controlled by an ICS. After a 4-week
run-in period, all patients were given beclomethasone 80
mcg twice daily. Weeks 3 and 4 of the run-in period provided baseline data. The treatment phase then consisted
of 14 weeks with beclomethasone 80 mcg twice daily plus
tiotropium 18 mcg once daily, or beclomethasone 160 mcg
twice daily, or beclomethasone 80 mcg plus salmeterol 50
mcg twice daily. Between each phase was a 2-week washout
period during which patients were given beclomethasone.
Patients receiving beclomethasone plus tiotropium had a
higher morning PEF than patients on doubled-dose ICS
(25.8 L/minute more, p<0.001). Tiotropium was also better with respect to evening PEF (difference of 35.3 L/
minute, p<0.001), prebronchodilator FEV1 (difference
of 0.1 L, p=0.004), proportion of asthma-control days
(difference of 0.079, p=0.01), daily symptom scores (difference of −0.11 points, p<0.001), and FEV1 after four
puffs of albuterol (difference of 0.11 L, p=0.003) than in
patients on doubled-dose ICS. Tiotropium was superior to
doubling of the ICS dosage for patients whose symptoms
were inadequately controlled while receiving beclomethasone alone at a dosage of 80 mcg twice daily (Peters
2010). Similarly, patients not controlled on high dosages of ICS plus LABA had either tiotropium or placebo
added, the mean FEV1 peak was significantly higher with
both tiotropium dosages than with placebo (difference of
5 mcg, 0.139 L, p<0.001), and 10 mcg, 0.170 L, p<0.001)
(Kerstjens 2011). Both 5 mcg and 10 mcg of tiotropium
delivered by the Respimat Soft Mist device are equivalent
to 18 mcg delivered by the HandiHaler (Caillaud 2007).
A similar trial investigated the long-term safety and efficacy of adding tiotropium (5 mcg by the soft-mist inhaler)
to patients on high-dose ICS plus LABA. Two replicate
randomized, double-blind, placebo-controlled, parallelgroup trials were conducted over a 48-week period. The
primary outcomes were FEV1 and length of time to first
severe asthma exacerbation. At 24 weeks, the mean difference in peak FEV1 between the tiotropium group and
the placebo group was 86 +/− 34 mL in trial 1 (p=0.01)
and 154 +/− 32 mL in trial 2 (p<0.001). The betweengroup difference in change from baseline trough FEV1 at
24 weeks was also significantly greater in the tiotropium
group versus placebo (88+/− 31 mL in trial 1, p=0.01, and
111+/− 30 mL in trial 2, p<0.001). The time to first exacerbation was increased by 56 days in the tiotropium group
over the placebo group (282 days vs. 226 days), which corresponded to a reduction of 21% in risk (hazard ratio 0.79;
95% CI 0.62–1.00; p=0.03). This group of trials showed
that tiotropium added sustained bronchodilation over
New Therapies in Asthma
24 hours and reduced severe exacerbations in patients
with asthma who had been symptomatic with persistent
airflow limitation despite the use of high-dose ICS plus
LABA (Kerstjens, 2012).
Given the effect of genetic polymorphisms on β-agonist
failure, alternatives to β-agonists are being investigated. One trial investigated patients with homozygous
Arg16 moderate persistent asthma who were receiving ICS (400–1000 mcg of budesonide or equivalent per
day). Patients were randomized to one of three arms:
tiotropium 5 mcg daily plus salmeterol placebo device;
salmeterol metered-dose inhaler 25 mcg two puffs twice
daily plus tiotropium placebo device; or placebo. Mean
weekly morning predose PEF was maintained during
the treatment period with tiotropium and salmeterol but
decreased for those on placebo. Tiotropium was noninferior to salmeterol (tiotropium minus salmeterol estimated
difference: −0.78; 95% CI −13.096 to 11.53, p=0.02), and
both tiotropium and salmeterol were superior to placebo
(Bateman 2011). Correspondingly, a 2009 trial examined
the impact of the addition of tiotropium on improved lung
function in patients with severe asthma. The investigators also sought to identify factors capable of predicting
a response to tiotropium by taking a pharmacogenetic
approach. Targeted genes were CHRM1, CHRM2, and
CHRM3 (which code for muscarinic receptors 1 to 3), and
ADRB2. The Arg16Gly polymorphism was significantly
associated with response to tiotropium (Park 2009).
Tiotropium can be recommended for patients with
severe persistent asthma who continue to be symptomatic
on high dosages of ICS and LABA (see Figure 1-2). Genetic
testing is not occurring extensively in clinical practice
because of cost and lack of routine insurance coverage
for such services. When genetic testing or sputum induction studies are available, the results can further guide
decision-making with regard to tiotropium. If a patient’s
asthma does not respond as assessed by symptom scores,
quality-of-life measures, or pulmonary function after an
8- to 12-week trial, tiotropium should be discontinued.
Differences in Inhalers
Since 2009, only albuterol hydrofluoroalkane (HFA)
metered-dose inhalers are permitted in the United States.
The HFA albuterol inhaler delivers a dose of albuterol (90
mcg per puff) comparable to that of the older chlorofluorocarbon inhalers. Patients may notice a different taste
and feel, because HFA inhalers emit a dose that uses less
force and has a smaller plume (Hendeles 2007).
Some differences exist between the three available
HFA albuterol inhalers (Table 1-4). Ventolin HFA contains only the drug and the propellant, which may lead to
better tolerability in some patients (Hendeles 2007). Also,
excipients added to ProAir HFA and Proventil HFA differ,
making the three products not interchangeable (BX rated)
(Orange Book 2012). Differences in spray characteristics
also influence patient reactions. A metered-dose inhaler
10
ACSAP 2013 • Pulmonary and Preventive Care
with a higher force may cause increased throat deposition,
whereas a lower spray temperature may cause a cold-Freon
effect. In both instances, the patient might stop inhaling
prematurely (Gabrio 1999). The cold-Freon effect was
common with the older chlorofluorocarbon inhalers,
but some data to suggest it may also occur with the HFA
inhalers.
One study collected the temperatures of emitted
plumes, the maximum compressive force, and the aerodynamic-particle-size distribution of ProAir HFA and
Ventolin HFA. The mean minimum plume temperatures
were significantly higher for ProAir HFA (7.2 +/−
0.7°C) compared with Ventolin HFA (−35.9 +/− 12.7°C,
p=0.0001). ProAir HFA produced a plume duration that
lasted 2.5 times longer than that of Ventolin HFA (385 +/−
46 microseconds vs. 156 +/− 58 microseconds, p=0.0001).
Also, the spray force of ProAir HFA was 55% lower than
that of Ventolin HFA (33.6 +/− 11.4 milli-Newton vs. 75.9
+/− 12 milli-Newton, respectively, p=0.0001). The ProAir
HFA product produced almost twice as many fine particles as did the Ventolin HFA inhaler (53 +/− 4 mcg vs. 26
+/− 2 mcg) (McCabe 2012).
The favorable spray characteristics of ProAir HFA (e.g.,
longer duration, lower impact, warmer plume, higher
number of fine particles) decrease the chances of the coldFreon effect. Additional studies comparing the pre- and
postbronchodilator FEV1 readings of the three different
HFA albuterol products would be useful for clinicians. A
switch to ProAir HFA may be warranted for patients who
experience the cold-Freon effect or who are unable to use
albuterol because of other negative spray characteristics.
New Directions in Asthma Assessment
Recent research has focused on the signaling molecule,
nitric oxide (NO), which is found in car exhaust emissions
and acid rain and which can deplete the ozone layer. In the
lung, this chemical acts as a vasodilator, a bronchodilator,
a nonadrenergic noncholinergic neurotransmitter, and an
agent of inflammation. Chemiluminescence can detect
exhaled NO; when a sample is mixed with ozone, a chemical reaction produces oxygen and nitrogen dioxide with
the emission of light. The amount of light measured by the
photodetector is proportional to the amount of NO in the
sample. Normal concentrations are 8 to 14 parts per billion (Yates 2001).
The fraction of exhaled NO may be an indicator of
eosinophilic inflammation in the airway. If the fraction is high, patients are more likely to respond to ICS
(Munakata 2012). Values greater than 50 parts per billion
in adults and greater than 35 parts per billion in children
can be used to indicate eosinophilic inflammation (Dweik
2011). Conversely, values less than 25 parts per billion
Table 1-4. Differences in HFA Albuterol MDI Characteristics
ProAir HFA
Proventil HFA
Number of
actuations to
prime inhaler
When to prime
Xopenex HFA
4
4
3
4
First-time use, not
used for >2 weeks
First-time use, not First-time use, not used
used for >2 weeks
for >2 weeks or when the
inhaler has been dropped
No
Yes
Protective pouch No
required before
dispensing?
Cleaning
Wash weekly with warm water; air dry
Expiration date
2 years
After all actuations
have been used
Proper storage
Any position
Any position
position
Plume
temperature
(°C)
Ventolin HFA
7.2 +/− 0.7
6 months after removal
from pouch
Upright position
(mouthpiece down)
−35.9 +/− 12.7
N/A
First-time use, not
used for >3 days
No
After all actuations
have been used
Upright position
(mouthpiece
down)
N/A
HFA = hydrofluoroalkane; MDI = metered-dose inhaler.
Information from manufacturer package inserts and McCabe JC, Koppenhagen F, Blair J, et al. ProAir HFA delivers warmer, lower-impact,
longer-duration plumes containing higher fine particle dose than Ventolin HFA. J Aero Med Pulm Drug Del 2012;25:104-9.
ACSAP 2013 • Pulmonary and Preventive Care
11
New Therapies in Asthma
in adults and less than 20 parts per billion in children
should be interpreted as low; therefore, responsiveness to
corticosteroids is less likely.
The tools to measure exhaled NO have yet to be standardized, and large population studies are needed to
determine the effect of confounding biases (Dweik 2011).
Therefore, routine tailoring of interventions based on
NO cannot be recommended at this time (Petsky 2009).
Providers can use the fraction of exhaled NO as an adjunctive tool when assessing patients with asthma. Also, if
patients report adherence to an ICS, yet their exhaled NO
readings remain high, further investigation on symptoms
and adherence may be warranted. The American Thoracic
Society’s position on exhaled NO is available online.
The FDA conducted a meta-analysis to investigate these
findings further, finding that LABAs increased the risk
of severe exacerbations driven by the number of asthmarelated hospitalizations, especially in children aged 4 to
11 years. The result was labeling changes to LABAs. To
ensure safe use, clinicians should recognize that LABAs
are contraindicated without a controller drug such as an
ICS and should be used chronically and long term only if
the patient’s asthma is not otherwise controlled. In addition, LABAs should be used for the shortest duration
possible, and their use in pediatric and adolescent patients
is restricted to the form of a combination product.
The Controversy Involving Long-Term LABA Use
The FDA’s 2008 review of the benefits and risks associated with the use of LABAs to treat patients with asthma
concluded that the benefits outweigh the risks, and therefore the drugs continued on the market. However, strict
label changes were enforced. Long-term use of LABAs
is appropriate only for patients whose asthma cannot be
managed without them (e.g., patients unable to remain
controlled on ICS monotherapy) (Kramer 2009). That
view differs from that of the National Asthma Education
and Prevention Program’s expert panel, as well as many
practicing clinicians who advocate reduction in ICS dose
of 25% to 50% over 3 months to the lowest dose possible
required (Chowdhury 2010; EPR-3 2007). Also, a recent
meta-analysis showed that in trials in which LABA therapy was discontinued in patients controlled on LABA plus
ICS, the LABA step-off approach resulted in increased
asthma impairment, worsening of asthma quality of
life questionnaire scores, and fewer symptom-free days
(Brozek 2012).
Pharmacists should encourage appropriate use of
LABA agents, being careful not to restrict their use for
patients who may derive benefit. The FDA mandated a
long-term safety study of LABA agents, and this trial is
ongoing. The results may help clarify this issue regarding
prescribing and recommending LABA agents.
Impulse Oscillometry
Impulse oscillometry is a forced oscillation technique
that can be used for diagnostic purposes when spirometry is not an option, such as in the frail elderly and in
young children (Tanaka 2011). The technique is delivered through an apparatus applied at the mouth. The
apparatus creates a wave of pressure (oscillation) that
gets transmitted into the lungs. The impulse oscillometry evaluates both respiratory resistance (i.e., the energy
required to propagate the pressure wave through the airways) and reactance (i.e., the amount of recoil generated
against the pressure wave at different oscillatory frequencies) (Komarow 2011). Use of the technique is gaining
momentum in diagnosis, evaluation of disease severity,
and assessment of response to drug therapy. The results
of the noninvasive and rapid technique can be correlated
with FEV1, FVC, and PEF (Song 2008), but spirometry
measures maximal forced respiratory efforts, and forced
oscillation measures quiet breathing. If the results of these
tests are not closely correlated, it does not imply that the
oscillation measurements are not valid (Smith 2005).
Recent Developments in
Pharmacotherapy
Step-Up Therapy for Pediatric Patients
There are limited data to guide practitioners’ decisionmaking when pediatric patients remain symptomatic on
low-dose ICS. The Best Add-on Therapy Giving Effective
Responses trial was a randomized, double-blind, threetreatment, three-period crossover trial for a total of 48
weeks (Lemanske 2010),. During each 16-week period,
subjects received either 250 mcg fluticasone twice daily, or
100 mcg fluticasone plus 50 mcg salmeterol twice daily, or
100 mcg of fluticasone plus 5 mg or 10 mg of montelukast
daily. The authors found that the response to LABA stepup was significantly more likely to be the best response
compared with montelukast (relative probability 1.6; 95%
CI 1.1–2.3, p=0.004) and the response to ICS step-up (relative probability 1.7; 95% CI 1.2–2.4, p=0.002). Similarly,
researchers investigated the combination of salmeterol
New Labeling Requirements for LABAs
Results of the Salmeterol Multicenter Asthma Research
Trial (SMART) showed that at baseline, the enrolled
patients had been on standard asthma therapy—including ICS (47% of whites, 38% of African Americans),
theophylline, leukotriene modifiers, or inhaled or oral
β-agonists (excluding salmeterol)—and randomized to
either salmeterol twice daily or placebo. That landmark
trial showed an increase in the number of respiratory- and
asthma-related deaths in the salmeterol group (13 out of
13,176 patients) compared with the placebo group (3 out
of 13,179 patients), with a relative risk of 4.37 (95% CI,
1.25–15.34, p<0.05). A subgroup analysis revealed that
the risk may be greater in African American patients compared with whites (Nelson 2006).
New Therapies in Asthma
12
ACSAP 2013 • Pulmonary and Preventive Care
and fluticasone versus doubling the dose of fluticasone in
pediatric patients with asthma (Vaessen-Verberne 2010).
Those authors found that the addition of salmeterol to
medium-dose fluticasone was not inferior to doubling the
dose of ICS with regard to symptoms during 6 months of
treatment.
There have been concerns that the use of LABAs in children may lead to increased risk of exacerbations. However,
a Cochrane analysis concluded that adding LABAs did
not increase exacerbations requiring oral steroids or hospitalizations when compared with ICS alone.
at improving asthma control as conventional practice. The
investigators also found SMART resulted in both lower
overall ICS dose (a reduction by approximately 300 mcg/
day of budesonide equivalents) and significantly lower
drug costs (by 25%) (Louis 2009).
Adverse effects most commonly seen with the
budesonide/formoterol combination in SMART trials included respiratory tract infection, pharyngitis,
rhinitis, bronchitis, sinusitis, headache, and aggravated
asthma (McCormack 2007); these were comparable with
rates seen when used conventionally (McGavin 2001).
The incidence of predictable adverse events—including palpitations, tachycardia, candidiasis, dysphonia, and
hoarseness—were low (ranging from 0%–2%).
Neither formoterol nor the formoterol/budesonide
combination has FDA label approval for use in the
treatment of acute symptoms. The practice of using combination products as both maintenance and reliever
therapy is neither routine in the United States nor mentioned in EPR-3; however, it is an option, according to
the Global Initiative for Asthma guidelines. It is an interesting and promising concept because using the same device
for both maintenance and acute symptoms is convenient
and could decrease device burden. Despite the aforementioned benefits of SMART, however, recommendation of
this practice is problematic. First, even though cost savings were seen with SMART, direct costs decreased;
drug utilization costs did not. Insurance and pharmacy
benefit providers would need to shift their current practice and begin providing more than 1-month supplies
of these expensive agents. Second, this practice is based
on evidence gained through randomized controlled trials that were conducted at both generalist and specialist
offices, where patients were closely monitored but whose
locations were outside the United States. Making the
leap from randomized controlled trial to clinical practice
can be challenging because both the providers and the
patients may be skeptical. Last, primary care providers
may be more comfortable waiting until a recommendation
to utilize SMART is addressed in the next EPR update.
Using LABA/ICS Combination Products
as Both Reliever and Controller
The concept of using either a device for single maintenance and reliever therapy (SMART) or adjustable
maintenance dosing is not new. Studies have shown that
formoterol can be an effective reliever agent (Barnes
2007) because of its rapid onset of effect (within 1 minute
to 3 minutes) and its long duration of action (12 hours or
more) (McCormack 2007). Formoterol causes systemic
adverse effects for approximately the same duration as
SABAs, which allows for cumulative doses of this drug to
be given (Barnes 2007). A real-life study was performed
in a diverse population of more than 18,000 patients. This
investigator found that using formoterol as a reliever drug
was as safe as using a SABA, and it resulted in both prolonged time to a first asthma exacerbation and reduced
drug requirements (Pauwels 2003).
The theoretical benefit of combination products is to
combine the bronchodilating effects of β-agonists with
the anti-inflammatory properties of ICSs when acute
therapy is warranted. By intervening early during the
time that patients experience debilitating symptoms and
deteriorating lung function, severe exacerbations may be
prevented (D’Urzo 2006). Study investigators hypothesized that patients on low-dose budesonide/formoterol
combination could also use a SMART device for delivery of their quick-relief drug. Such use would enable
patients to simultaneously obtain effective and rapid relief
from symptoms and adjust their anti-inflammatory therapy at times of greatest need (O’Byrne 2005). That study
was groundbreaking because it demonstrated that the
budesonide/formoterol combination for both maintenance and quick relief significantly reduced total severe
exacerbations, avoided exposure to oral corticosteroids,
reduced reliever-drug use, and relieved nighttime symptoms, including awakenings, and mild exacerbation days
when compared with budesonide/formoterol or highdose budesonide for maintenance (both with SABA for
quick-relief use) (O’Byrne 2005). The concept has been
validated by several other studies. Under the SMART
approach, patients had decreased rates of severe exacerbations and associated medical care (Kuna 2007; Rabe
2006a; Rabe 2006b). Similarly, in an open-label trial of
908 patients, SMART was found to be at least as effective
ACSAP 2013 • Pulmonary and Preventive Care
Treating Small Airway Disease
Asthma is an inflammatory disease that affects the
respiratory tract; it extends to the peripheral airways
that are less than 2 mm in diameter (sometimes referred
to as the small airways). When small airway disease is
suspected, the studies that commonly assess airflow measure forced expiratory flow rates at 50% of vital capacity
(FEF50%) and at 25% to 75% of vital capacity (FEF25%-75%).
Airway resistance, too, can be measured by impulse oscillometry. Peripheral airway inflammation can also be
assessed by the fractional excretion of NO (van den Berge
2011).
Newer inhalation devices enable drugs to better target those small airways. The newer HFA devices generate
smaller particles, with an average size of 1 micrometer.
13
New Therapies in Asthma
Examples of HFA ICSs are beclomethasone, flunisolide,
and ciclesonide. These small-particle HFA metered-dose
inhalers result in higher lung deposition compared with
conventional dry powder inhalers (50% to 60% vs. 10% to
20%) and lower oropharyngeal deposition (30% to 40%
vs. more than 80%) (van den Berge 2011). Typical ICS formulations (fluticasone, beclomethasone, and budesonide)
deliver relatively large particles (more than 3 micrometers) that do not penetrate into the small airways (Johnson
2012). Systemic adverse effects of the HFA formulations compared with their chlorofluorocarbon (CFC) or
dry powder inhaler counterparts vary. No decrease in
either urinary or serum cortisol levels were found with
HFA beclomethasone compared with CFC beclomethasone (van den Berge 2011). However, small studies have
shown differences in growth velocity between HFA and
CFC budesonide in favor of the CFC formulation in children (Gentile 2010). These small-particle ICS agents are
equally as effective as the conventional dry powder inhaler
agents. For example, results of comparative clinical trials
demonstrated that HFA beclomethasone is equivalent
to fluticasone (a more potent corticosteroid) at the same
dose in maintaining asthma control (Gentile 2010).
Further efficacy and safety studies are needed to confirm
the advantages of these small-particle ICS agents. In particular, long-term prospective trials evaluating patients
with uncontrolled disease despite adherence to a largeparticle ICS agent would be helpful.
recommend omalizumab cautiously in patients with
known factors that put them at risk of myocardial infarction or stroke.
Leukotriene Modifiers and Suicide
In 2008, the FDA investigated a possible association between the use of montelukast and suicide or
suicidal behavior. In 2009, the package inserts for montelukast, zafirlukast, and zileuton were updated to include
neuropsychiatric events. A population-based cohort study
of patients exposed to one or more prescriptions for montelukast from 1998 to 2007 revealed that among 23,500
patients, one case of suicide occurred in a 61-year-old
woman. The patient had been given one prescription for
montelukast 2 years before her death, and montelukast
was ruled out as the cause (Jick 2009). Other investigators have also been unable to link montelukast to suicide
risk (Schumock 2012; Schumock 2011). When prescribing leukotriene modifiers, clinicians are urged not to
withhold warranted therapy but to monitor patients for
neuropsychiatric effects.
Emerging Therapies
Bronchial Thermoplasty
Bronchial thermoplasty involves the distribution of
radio frequency energy into the airways by flexible bronchoscopy to reduce airway smooth muscle mass and
decrease bronchoconstriction (Thomason 2011; Wahidi
2011). The electrical energy is delivered through electrodes and is then converted to heat when it comes in
contact with tissue (Wahidi 2011). Thermal energy is
delivered to the airway wall in a series of three bronchoscopies that take place 3 weeks apart: The first procedure
treats the airways of the right lower lobe; the second, the
airways of the left lower lobe; and the third, the airways
of both upper lobes (Duhamel 2010). When heat is introduced to the smooth muscle of the airway, actin-myosin
interaction is disrupted from denaturization of motor proteins, thereby quickly inactivating muscle cells (Gildea
2011).
In 2010, the bronchial thermoplasty received label
approval for use in the treatment of patients 18 years or
older with severe persistent asthma not well controlled
with ICS and LABA (Wahidi 2011). The FDA is requiring
phase 4 postmarketing surveillance studies. This therapy
is not currently covered by most private insurance plans,
which limits its clinical acceptance. Once that barrier has
been overcome, interventional pulmonologists as well as
bronchoscopists’ advanced skills, training, and expertise
will be needed for this newly approved technique.
Targeting airway smooth muscle with bronchial thermoplasty is logical because of bronchial thermoplasty’s
role in bronchoconstriction, promotion of inflammation and airway remodeling, and the expelling of mucus
from the lungs. The Asthma Intervention Research (AIR)
Risks with Omalizumab
Anaphylaxis Omalizumab, a 95% humanized monoclonal antibody
that binds to circulating IgE, is currently approved for
moderate to severe persistent allergic asthma and for those
patients not well controlled on combination medium
dosages of ICS and LABA. A boxed warning related to anaphylaxis has been added, and patients should be observed
in the clinician’s office for 2 hours after each of the first
three injections and for 30 minutes after each subsequent
dose, because 75% of reported anaphylaxis cases occurred
within those periods (Cox 2009). The risk evaluation and
mitigation strategy program for omalizumab was discontinued in 2011; however, a patient medication guide is still
required. Patients should have access to self-injectable
epinephrine and be educated on the signs and symptoms
of anaphylaxis and on the administration of self-injectable
epinephrine.
Atherothrombotic Events
A link between omalizumab use and arterial thrombotic events reported to the FDA Adverse Event Reporting
System has been investigated. Myocardial infarction
and stroke accounted for the majority of the events. In
light of the findings, future robust epidemiologic studies
are needed to evaluate that potential, adverse effect (Ali
2011). Until such evidence is available, clinicians should
New Therapies in Asthma
14
ACSAP 2013 • Pulmonary and Preventive Care
trial study group randomized patients to either bronchial
thermoplasty or control. The mean number of mild exacerbations was 0.18 +/− 0.31 per subject per week in the
bronchial thermoplasty arm 12 months after treatment,
compared with 0.35 +/− 0.32 at baseline. The number of
mild exacerbations in the control group was 0.31 +/− 0.46
per subject per week compared with 0.28 +/− 0.31 from
baseline. The difference between the two groups was significant at months 3 (p=0.03) and 12 (p=0.03). Patients
who received bronchial thermoplasty had 10 fewer mild
exacerbations per subject per year. If treated with ICS
monotherapy, the patients receiving bronchial thermoplasty had a further reduced rate of mild exacerbations
(Cox 2007).
Similarly, the Research in Severe Asthma (RISA) study
group (Pavord 2007) investigated patients with severe
asthma. Bronchial thermoplasty was associated with a
short-term increase in morbidity (e.g., worsening asthma
symptoms, increased rescue medication use, decreased
quality of life and asthma control) in the period immediately after treatment. The use of rescue drugs improved
lung function and asthma-related quality of life scores,
which remained statistically significant up to 52 weeks
after treatment (Pavord 2007). When analyzed together,
the results of the AIR and RISA trials indicate that the
numbers of adverse events were similar across studies but
were worse in patients with more severe disease. Adverse
events reported included wheeze, breathlessness, chest
tightness, cough, dyspnea, asthma exacerbation, and episodes of lobar segmental collapse. The authors did not,
however, show any deterioration in lung function over 3
years, and CT scans showed no evidence of abnormal airway structure or injury to lung tissue (Cox 2009).
In a sham-controlled trial, bronchial thermoplasty
led to improvements in severe exacerbations that would
have required corticosteroids, emergency department
visits, and time lost from work or school during the time
after receiving bronchial thermoplasty (Castro 2010).,
Similarly, a trial assessed the safety of bronchial thermoplasty 5 years after treatment and found that neither the
rate of oral corticosteroid usage nor the proportion of subjects requiring oral corticosteroid pulses therapy showed
any worsening over the period in the bronchial thermoplasty group. In the bronchial thermoplasty group, 57%
reported decreases in LABA usage over those 5 years
(Thomson 2011).
Bronchial thermoplasty is an additional option for the
management of patients with severe or refractory asthma.
This newly approved procedure is both safe and effective
and should be recommended accordingly.
that use toll-like receptors (TLRs) (Fonseca 2009). The
TLRs detect nonself and then activate both branches of the
immune system. The TLRs bind to and are stimulated by
unmethylated cytosine-phosphate-guanine dinucleotides
in microbial DNA sequences (Gupta 2010); this leads to
intracellular signaling (Sequin 2009) and the production of
cytokines and chemokines (Parkinson 2008).
Similarly, CD4 T cells play a role in atopic conditions
such as asthma. These cells can be separated into Th1
and Th2 cell types (see Figure 1-1). The hygiene hypothesis implicates Th2 in allergic diseases. Immunotherapy,
or allergy shots, are believed to attack allergens by altering the immune response to Th2 and Th1. Activation of an
antigen-presenting cell leads to secretion of chemokines
and cytokines in the airway that in turn promote CD4
cell activation. That cell activation then augments CD4
cells’ differentiation into Th1 cells. Oligonucleotides can
replicate that reaction (Gupta 2010). Shifting the balance
away from Th2-mediated response and toward the innate
Th1 aspect can modify allergic or atopic diseases such as
asthma. This has been shown in both animal and human
trials. Administering both allergen and oligonucleotides
to sensitized mice promoted Th1 responses and inhibited
IgE production (Sequin 2009).
It was hypothesized that patients treated with unmethylated cytosine-phosphate-guanine dinucleotides would
have a lessened allergic response. Patients with mild atopic
asthma were given the inhaled oligonucleotide 1018 ISS
followed by either an allergen inhalation challenge or placebo 24 hours later. Although 1018 ISS was demonstrated
to be pharmacologically active, the 4-week treatment
duration may have been insufficient to induce immunotherapy in human atopic disease (Gauvreau 2006). The
oligonucleotide ASM8 reduces the allergen-induced early
asthma response with a trend for a reducing late-asthmatic
response. Trials have also evaluated oligonucleotides as
adjuvants to immunotherapy; these hold promise because
oligonucleotides are strong inducers of the Th1 response
(Senti 2009).
Another emerging target for treatment of asthma specifically involves the TLRs because they are expressed
on epithelial, smooth muscle, mast, and fibroblast cells.
Activation of TLRs can induce a strong Th1 showing by
modulating a response that commits T-helper cells to a Th1
over the Th2 phenotype (Meng 2011). That down-regulation of the Th2 response leads to fewer manifestations of
allergic diseases and asthma (Fonseca 2009). Research has
centered on TLR 3, TLR 7, and TLR 9, and specific agents
are currently in phase I and II clinical trials (Table 1-5).
The lung is an ideal target for oligonucleotide and TLR
therapy because of delivery by inhalation, prolonged duration of action in the lung, and little systemic toxicity. Still,
these therapies face some challenges, including in vivo stability and the possibility of adverse effects such as immune
stimulation, inflammation, and possible hypersensitivity
or bronchoconstriction of the airway (Sequin 2009).
Oligonucleotides
The immune system branches into either innate or adaptive-mediated immunity that facilitates discrimination
between self and nonself. The innate immune system is activated by early exposure to microbes, bacteria, and viruses
ACSAP 2013 • Pulmonary and Preventive Care
15
New Therapies in Asthma
Table 1-5. Emerging Asthma Therapies in Clinical Development
Classification
Oligonucleotide
agents
Experimental Agents
ASM8
1018 ISS
AVE 0675
HYB 2093
CYT 003-QbG10
AIR 645
GSK 2245035
AZD8818
AVE 0675
IMO-2134
SAR 21609
MK-7246
OC0000459
ARRY-005
ACT-129968
AMG 853
Mepolizumab
Reslizumab
Benralizumab
(MEDI-563)
Mechanism
Promotes Th1 over Th2
response.
Inhibits IgE production
Efficacy/Safety
Decreases allergeninduced early and late
asthmatic response
Anticipated Benefit
Symptomatic patients
already receiving
immunotherapy
Modulates T-helper
cells to a Th1 over the
Th2 phenotype
Theoretical risk of
overstimulating the
immune system and
inducing autoimmune
diseases
Improvement in FEV1,
reduction in total IgE,
and trend for reduction
of sputum eosinophils
Not yet known
Reduces exacerbation
rates and eosinophil
counts in both blood
and sputum
Monoclonal
antibodies
targeting IL-4
Alrakincept
Pascolizumab
(SB240683)
Pitrakinra (Aerovant or
AER 001)
AMG 317
Monoclonal
antibodies
targeting IL-9
MEDI-528
Monoclonal
antibodies
targeting IL-13
Tralokinumab
(CAT-354)
Anrukinzumab
(IMA-638)
QAX576
IMA-026
Lebrikizumab
(MILR1444A)
Blocking IL-4
Statistically significant
decreases IgE
changes in ACQ were
production, mucus
not met; however,
hypersecretion, airway
patients receiving
hyperresponsiveness,
highest-dose pitrakinra
and inflammatory
experienced fewer
cellular influx
exacerbations vs.
placebo
Theoretically,
Small, phase 2 study
decreases mast cell
showed no effect on
infiltration of the lung,
FeNO or the late
up-regulation of IL-13
asthmatic response
and IL-5, eosinophil
infiltration, AHR, and
mucus production
Theoretically blocks
Small, phase 1 study
AHR, eosinophilic
showed a T1/2 of 12
inflammation, and
to 17 days and can be
mucus hypersecretion
safely administered to
patients with asthma
Patients still
symptomatic
on conventional
therapy and chronic
oral corticosteroids
Symptomatic patients
with atopic disease
Patients with higher
reversibility appear
to have better
responses
Patients with high
ACQ scores
Not yet known
Toll-like receptor
agents
CRTH2
antagonists
Monoclonal
antibodies
targeting IL-5
CRTH2 is a marker for
Th2 cells
Reduces production,
activation, and
proliferation of
eosinophils
Not yet known
Not yet known
(continued)
New Therapies in Asthma
16
ACSAP 2013 • Pulmonary and Preventive Care
Table 1-5. Emerging Asthma Therapies in Clinical Development (continued)
Classification
Experimental Agents
Mechanism
Efficacy/Safety
Anticipated Benefit
Drugs targeting
TNF-α
Infliximab
Etanercept
Golimumab
(CNTO-148)
Reduction of TNF-α
can lead to reduction
in BHR and sputum
neutrophils
Short-term efficacy seen
in patients with severe
disease.
The dose of oral
corticosteroids may be
able to be reduced after
initiation with a TNF-α
agent.
Safety concerns with
golimumab include
malignancies and
pneumonia
Patients with FEV1
<60% predicted, 49
years or older, and
those with onset of
asthma at age 12
years or older
ACQ = Asthma Control Questionnaire; AHR = airway hyperresponsiveness; BHR = bronchial hyperresponsiveness; CRTH2 = chemoattractant
receptor-homologous molecule; FeNO = fractional exhaled nitric oxide; IL = interleukin; Th = T-helper (cell); TNF-α = tumor necrosis factor–alpha.
Information from Catley MC, Coote J, Bari M, Tomlinson KL. Monoclonal antibodies for the treatment of asthma. Pharmacol Ther
2011;132:333-51; Cho JY. Recent advances in mechanisms and treatments of airway remodeling in asthma: a message from the bench side to
the clinic. Korean J Intern Med 2011;26:367-83; Corren J, Busse W, Meltzer EO, Mansfield L, et al. A randomized, controlled, phase 2 study
of AMG317, an IL-4Rα antagonist, in patients with asthma. Am J Respir Crit Care Med 2010;181:788-96; Dimov VV, Stokes JR, Casale TB.
Immunomodulators in asthma therapy. Curr All Asthma Rep 2009;9:475-83; Desai D, Brightling C. Cytokine and anti-cytokine therapy in
asthma: ready for the clinic? Clin Exp Immunol 2009;158:10-9; Ferrari N, Seguin R, Renzi P. Oligonucleotides: a multi-targeted approach for
the treatment of respiratory diseases. Future Med Chem 2011;3:1647-62; Gauvreau GM, Boulet LP, Cockcroft DW, et al. Antisense therapy
against CCR3 and the common beta chain attenuates allergen-induced eosinophilic responses. Am J Respir Crit Care Med 2008;177:952-8;
Kanzler H, Barrat FJ, Hessel EM, et al. Therapeutic targeting of innate immunity with toll-like receptor agonists and antagonists. Nature Medicine
2007;13:552-9; Nguyen T-HT, Casale TB.
Chemoattractant Receptor-Homologous Molecule
Researchers have identified chemoattractant receptor-homologous molecule (CRTH2) as a marker for
human Th2 cells (Chevalier 2005). New evidence is
mounting surrounding the role of prostaglandin D2,
which is thought to elicit actions through the D-type
prostanoid receptor. The prostaglandin binds to CRTH2
(Schuligoi 2010) and indomethacin. Scientists have used
indomethacin, a CRTH2 agonist, as a starting block and
have prepared novel CRTH2 DP2-selective antagonists
(Birkinshaw 2006). Both CRTH2 and prostaglandin D2
are promising targets for antiasthma drug therapy (see
Figure 1-1).
A novel CRTH2 antagonist, MK-7246, is reversible and
highly selective for the human CRTH2 receptor (Gervais
2011). An oral CRTH2 antagonist (OC0000459) showed
a 7.4% improvement in FEV1 at 28 days (p=0.037). The
OC0000459 agent also led to a reduction in total IgE
concentration and a trend toward decreasing sputum
eosinophils (Barnes 2012).
the release of cytokines; this initiates differentiation into
either Th1 or Th2 cells. On one hand, interleukin-1, IL-6,
and transforming growth factor–β induce Th17, IL-12, and
interferon-gamma (IFN-γ)-promoting Th1 cell development. On the other hand, IL-4, IL-25, IL-33, and thymic
stromal lymphopoietin drive Th2 differentiation (Desai
2009). Severe or refractory steroid-resistant asthma could
be the result of a dominant Th1 phenotype using tumor
necrosis factor–alpha (TNF-α), IFN-γ, IL-17, and IL-27.
Using that theory, researchers have targeted single cytokines that are thought to play dominant roles (see Figure
1-1).
Anti-IL-5
Two humanized anti-IL-5 therapies are undergoing premarket analysis. Mepolizumab, which is
under investigation and in preclinical development by
GlaxoSmithKline, reduces the production, activation, and
proliferation of eosinophils (Smith 2011). Mepolizumab
decreases exacerbation rates and the eosinophil counts in
both blood and sputum (Halder 2009); it also allows for
reductions in oral corticosteroid dosage without the risk
of exacerbations (Parameswaran 2009). Mepolizumab
reduces the number of asthma exacerbations experienced per year (Pavord 2012). This is an exciting advance
for patients with uncontrolled severe asthma because it
appears to be a safe and effective option that could lead to
withdrawal of oral corticosteroids.
Anticytokine Therapy
With the development of omalizumab, enthusiasm
surrounding the identification and use of new biologics
continues. Mast cells are important sources of cytokines,
chemokines, proteases, prostaglandin D2, and histamine
(Desai 2009). In the respiratory epithelium, dendritic
cells network with the innate immune system, leading to
ACSAP 2013 • Pulmonary and Preventive Care
17
New Therapies in Asthma
TNF-α Blockade
Derived mainly from lymphocytes, mast cells, and
macrophages, TNF-α leads to both increased bronchial
hyperresponsiveness and sputum neutrophils and is an
attractive target for severe asthma (Wenzel 2009). The
use of anti-TNF-α agents has been shown to be effective
in other inflammatory diseases such as rheumatoid arthritis and Crohn disease. Data with existing TNF-α agents
such as etanercept for asthma show short-term efficacy
for severe disease, but in patients with milder disease, its
efficacy is modest (Antoniu 2009). Infliximab has limited data, suggesting that patients with moderate asthma
uncontrolled by monotherapy with an ICS may experience fewer exacerbations (Erin 2006). A case series of
12 patients with concomitant rheumatoid arthritis and
asthma who were taking etanercept (n=5), infliximab
(n=3), or adalimumab (n=4) revealed that in those on oral
corticosteroids, the dose could be reduced after initiation
of the TNF-α inhibitor, and yet wheezing improved. Also,
upon discontinuation of the TNF-α inhibitor, wheezing
resumed (Stoll 2009).
A phase 2 study of golimumab in patients with severe
persistent asthma was ended early at week 24 because
of safety concerns that included increased incidence of
malignancies (8 reported out of 231 patients) and infections such as pneumonia (Wenzel 2009). Subgroup
analysis revealed a trend toward a lower risk of asthma
exacerbations with golimumab versus placebo in the following subgroups: (1) patients 49 years or older, (2)
patients with more than one ED visit or hospitalization
in the year before the study, (3) patients with baseline
prebronchodilator FEV1s less than 60% predicted, and
(4) patients with asthma onset at 12 years of age or older
(Wenzel 2009). Given the role of TNF-α in severe, refractory, or steroid-resistant asthma, future studies on the use
of this anticytokine are needed to identify whether the
long-term risk-benefit profile favors use in asthma.
whose asthma is poorly controlled should be assessed
much more frequently (EPR-3, 2007). Print versions of
the Asthma Control Test are available, as are online interactive tools that score and evaluate results for patients.
Overall, control of asthma is based on two components:
(1) current signs or functional status; and (2) future risk of
exacerbations. Typically, the worse the current signs, the
higher the future risk. Patients often view control of their
disease differently than their care providers. For example,
survey data show that 32%–49% of patients experiencing
severe asthma symptoms and 39%–70% of patients with
moderate symptoms said their current level of asthma
control was “well controlled” or “completely controlled”
(Rabe 2004). Pharmacists are encouraged to educate
patients not simply to accept symptoms and disruptions
in their life but also to better understand what constitutes
well-controlled asthma, and that controller adherence is
a means to that end. Pharmacists should discuss Asthma
Control Test results with patients and communicate such
findings to providers.
Quality of life should be assessed periodically. Quality
of life for children with asthma has been defined as the measure of emotions, asthma severity, symptoms, emergency
department visits, missed school days, and activity limitations (Walker 2008). Pharmacists should ask patients,
“Since your last visit, how many days did your asthma
cause you to miss work or school, disturb your sleep, limit
your activities, or cause an unscheduled visit to the ED or
a hospital stay?” Validated questionnaires are available to
gain an appreciation of how asthma affects quality of life.
Clinical pharmacists should monitor for drug-related
issues such as adherence or adverse events patients may
be experiencing. Nonadherence with controller agents
increases the risk of poor outcomes and additional health
care costs. An analysis of e-prescription and filled-claims
data revealed that 24% of first-time prescriptions were
never picked up by patients (Fischer 2011). Factors associated with nonadherence included nonformulary status
and cost of copayment.
Patients who fill first-time prescriptions in a lower
copayment tier are more likely to refill them (Fischer
2011). Pharmacists should ensure prescriptions are covered on a patient’s formulary at the lowest copayment tier.
If available, controller drugs should be set up for automatic refill, thereby ensuring monthly fills and reminders.
Pharmacists should assist uninsured patients to obtain
drugs through manufacturers’ patient assistance programs, local asthma coalitions, or channels developed
by local chapters of national organizations such as the
Asthma and Allergy Foundation of America.
Future Studies with Anticytokines
Multiple preclinical trials are evaluating specific markers related to the asthma inflammatory cascade. The
results of trials involving agents targeting IL-4, IL-13,
IL-9, IL-12, IL-10, interferon-γ, granulocyte-macrophage
colony-stimulating factor, and even Th17 cells are anticipated (Hansbro 2011; Desai 2009). As understanding of
the cytokine networks continues to evolve, so too will the
potential targets for antiasthma therapy.
Monitoring
Once patients are taking appropriate maintenance
drugs, the emphasis turns to control. The patient’s level of
control should be assessed at each follow-up appointment
(see Box 1-2). Patients who have well-controlled asthma
can be seen every 6 months; patients whose asthma is less
well controlled must be seen more routinely; and patients
New Therapies in Asthma
Patient Education
Education for patients with asthma is multifaceted
because it should cover the disease process; drugs, including proper inhalation and device technique; written
18
ACSAP 2013 • Pulmonary and Preventive Care
asthma action plans; and proper use of a peak flow meter.
Coaching on how to manage acute symptoms and when to
seek emergent care is also required. With their extensive
knowledge of pathophysiology and therapeutics, pharmacists are suited to provide such educational services as
part of the health care team.
Device technique instruction is imperative because
improper use leads to poor outcomes. Regardless of the
device selected, patients should be initially instructed on its
use. ▶ play video Adding a physical demonstration to both
oral and written instructions is an effective way to improve
device technique (Bosnic-Anticevich 2010). Routine
review of proper technique is important: in one study, a
decline in proper technique occurred with a time gap of just
2 months between teachings (Bosnic-Anticevich 2010).
Also, repeated instruction over time improves regimen
adherence (Takemura 2010). Patients should be instructed
to bring all inhalers to appointments so that device technique can be assessed and documented frequently. Charting
education topics and specifics regarding a patient’s technique is helpful for the next follow-up. For patients with low
literacy levels or who are nonnative speakers, technology
aids may be appropriate. Videotaped instructions or computer-aided systems, as well as cartoons and pictographs,
can be helpful (Kessels 2003).
Asthma self-management is often linked to education,
behavioral modification, and trigger avoidance. Giving
explicit instructions through a written asthma action
plan provides patients with information to manage both
chronic therapy and acute symptoms. Pharmacists should
assess patients’ baseline knowledge, determine whether
any important cultural beliefs exist, and promote communication between patient and provider. If the beliefs and
expectations of a health care provider differ from those of
the patient—especially if the two have different cultural
backgrounds or ethnicities—adherence can be impeded
(Poureslami 2007). Open discussion about perspectives
and beliefs facilitates communication between providers
and patients and helps ensure that both perspectives are
understood and negotiated (Poureslami 2007). By ensuring
that patients understand the significance of adherence with
their controller agents, treatment failure may be avoided.
Some patients have the common misconception that
once their symptoms start to improve, the drug is no longer needed. Conversely, prescribers usually think every
prescription written gets filled, picked up in a timely
manner, used as directed, and refilled on time. Clinical
pharmacists can educate both parties, including coaching
patients on adherence and updating prescribers on actual
patient drug use.
well as increasing the proportion of patients receiving care
according to the guidelines. The report pinpoints the need
for written asthma management plans and formal patient
education. Clinic- or community-based clinical pharmacists may help meet those targets by (1) monitoring the
appropriateness of treatment plans, (2) educating patients
on a written self-management plan, drugs, and device
technique; and (3) and providing formal education related
to the patients’ disease.
Practice Management
The role of clinical pharmacists in assisting or managing patients with asthma has been documented (Bunting
2006). In the community setting, pharmacists who integrate routine, brief asthma interventions into their daily
work flow increase pharmacist-provider exchanges and
successfully reach a large number of patients (Berry 2011).
Taking advantage of frequent contact with patients during
monthly refill encounters is an easy way to assess patients’
asthma knowledge, discuss inhalation technique, and
answer questions.
Pharmacists as Certified Asthma Educators
To become a certified asthma educator (AE-C), a pharmacist must pass a national examination created and
maintained by the National Asthma Educator Certification
Board (NAECB). The mission of the NAECB is to “promote
optimal asthma management and quality of life among individuals with asthma, their families, and communities by
advancing excellence in asthma education through the certified asthma educator process.” Over 3000 asthma educators
nationwide range from physicians, nurses, and respiratory
therapists to community asthma educators; about 3% are
pharmacists. In a survey of certificants, the majority of
AE-Cs spend their time discussing asthma action plans;
developing asthma programs; providing asthma education; offering, coordinating, or arranging asthma services;
diagnosing or managing asthma; and performing and interpreting spirometry (Cataletto 2011). Pharmacists are
excellent AE-C candidates because their education, training, and unique appreciation for drug, device, and patient
education techniques are highly valued.
Professional development, added responsibilities,
and job satisfaction are linked to becoming certified as
a pharmacist (Cataletto 2011). Whether asthma education performed by pharmacists will be reimbursable in
the future is unknown. However, the AE-C credential is
recognized in many arenas of health care, and in some
instances, is required for reimbursement by third-party
payers.
Asthma education delivered by health professionals is
important to the patient’s overall care. For example, AE-Cs
can help ensure patients understand disease pathology,
the roles of controller and reliever drugs, the importance of adherence, how to monitor for acute changes in
Quality Improvement
The Healthy People 2020 report targets several areas for
improvement of asthma outcomes, including reducing
asthma-related ED visits, hospitalizations, and deaths, as
ACSAP 2013 • Pulmonary and Preventive Care
19
New Therapies in Asthma
References
symptoms, how to follow a written asthma action plan,
and proper device technique. Further information on
becoming an AE-C and on the self-assessment examination as well as the candidate handbook, containing a
detailed content outline of the examination, are available
online.
Ali AK, Hartzema AG. Assessing the association between
omalizumab and arteriothrombotic events through
spontaneous adverse event reporting. J Asthma All 2012;5:1-9.
PubMed Link
Antoniu SA. Cytokine antagonists for the treatment of asthma.
Progess to date. Biodrugs 2009;23:241-51.
PubMed Link
Role of Technology
An increasing proportion of patients are technologically savvy. By 2015, a projected 65% of U.S. residents will
have smartphones or tablet devices. The largest growth in
smartphone ownership is among individuals 18 to 24
years old and those 45 to 54 years old (Gahran 2011). Free
and low-cost smartphone applications are available to
assist patients with asthma management. My Asthma Log
enables patients to log asthma exacerbations and enter
appointment dates. This application includes information on asthma drugs as well as links to videos on device
technique. AsthmaSense includes a journaling feature,
medication compliance reminders, and emergency contact information; it also offers users the ability to share
data with caregivers. Plans are to improve this application
with integrated sensors that will detect environmental
changes in air quality and weather. Abriiz is marketed as
a comprehensive asthma management system that lets a
patient or caregiver create an online portal with information uploaded from a mobile device, as well as adherence
features. Information is easily transmitted to a clinician
for review. A loan-to-own program is available for eligible
patients without access to a smartphone.
Other technological advances may improve compliance. The Asthmapolis sensor attaches to a rescue inhaler
to collect data on when and where a patient experiences
asthma symptoms. The sensor communicates with the
patient’s smartphone or base station and transmits the
usage data, including location and time; this may include
environmental triggers such as air quality or pollen levels. With the use of advanced technology and social media
on the rise, pharmacists should be encouraged to become
well versed in platforms that can help patients to better
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Conclusion
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As the prevalence of asthma rises, more health care
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help prevent acute exacerbations, ED visits, and hospitalizations by promoting controller drug adherence.
Individuals with asthma require significant education
related to the disease state, drug therapy, and device technique, which should be reinforced routinely. In the future,
new targeted therapies may interfere with the underlying pathophysiology of asthma, its pharmacogenomics, or
both, which may result in improved patient outcomes.
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ACSAP 2013 • Pulmonary and Preventive Care
25
New Therapies in Asthma
Self-Assessment Questions
1. A 32-year-old woman (height 5′4″, weight 189 lb)
with persistent asthma complains of shortness of
breath (SOB) and wheezing twice weekly. She uses
her albuterol hydrofluoroalkane (HFA) inhaler two
times a week, usually when outside at the park. She
wakes up at night coughing about once weekly. Her
current drugs include albuterol HFA 1-2 puffs every
4–6 hours as needed for SOB, fluticasone/salmeterol
diskus 250/50 one puff twice daily, loratadine 10 mg
once daily for “allergies”, fluticasone nasal spray 50
mcg 2 sprays each nostril once daily, and metformin
500 mg twice daily. Sertraline 50 mg once daily was
initiated 2 months ago. She does not have a peak flow
meter but follows her asthma action plan. The patient
cannot remember the last time she had to visit the
emergency department (ED) for an exacerbation. Her
medical history includes allergic rhinitis, depression,
and polycystic ovary syndrome. Her BP is 110/76 mm
Hg. Which one of the following would best address
this patient’s current symptoms?
C. His chances are quite good because of past
exacerbation history and Mom with asthma.
D. The chance of continued asthma is low and he
should grow out of his asthma by age 10.
Questions 3 and 4 pertain to the following case.
Y.P. is a 26-year-old man who comes in to pick up a refill
on his Ventolin HFA inhaler. He is asked to demonstrate
his inhalation and device technique. ▶ play video
3. Which of the following is the most appropriate feedback on Y.P.’s inhalation technique?
A. Breath holding for 5 seconds and exhalation for 5
seconds after your dose was appropriate for drug
deposition.
B. The mouthpiece doesn’t need to be inspected if
lid was sealed and the canister does not need to
be shaken.
C. Your slow inhalation rate and total time spent
inhaling of 2 seconds was adequate
D. The pause during inhalation and resumption
with one more second of inhalation may result in
less drug reaching your lungs.
A. Add montelukast 10 mg once daily at bedtime.
B. Discontinue fluticasone/salmeterol combination.
Initiate fluticasone 250 mcg diskus 1 puff twice
daily
C. Discontinue fluticasone/salmeterol combination.
Initiate fluticasone 250 mcg diskus 2 puffs twice
daily.
D. Add theophylline 200-mg sustained-release
tablet once daily.
4. Which one of the following is best for Y.P. at this time?
2. A 30-month old boy with asthma presents for a followup appointment accompanied by his mother, father,
and paternal grandmother. The boy has visited the ED
five times in the past year for exacerbations and was
admitted to the pediatric intensive care unit twice in
the past year for asthma treatment. His family history includes asthma (mother, maternal grandfather),
hypertension (paternal grandfather), and allergic rhinitis (father). The patient’s mother smokes but not
in the house or car. His laboratory tests show blood
eosinophilia: 3%, sputum: predominant eosinophils.
The patient’s father is a high school basketball coach
and is very concerned about his son’s ability to play
sports in school. The family asks you what the chances
are that the boy will continue to have asthma as a
teenager and adult. Which one of the following is the
best response to this family’s query?
5. A 35-year-old African American man has very poorly
controlled persistent asthma. His current drugs
include mometasone 200 mcg twisthaler 1 puff twice
daily, formoterol aerolizer 12 mcg capsule inhaled
twice daily, prednisone 5 mg once daily, albuterol
HFA 1-2 puffs every 4–6 hours as needed for SOB,
and omeprazole 20 mg once daily. The patient uses a
phone alarm to remind him when to take his drugs
and inhalations on time. Refill histories show he is
adherent. He wants his breathing to be better controlled and says he has been doing research online. He
asks if he should get his “genes tested.” Which one of
the following is the best response to this patient?
A. Change to ProAir HFA as rescue medication.
B. Educate further on appropriate inhalation
technique.
C. Change to Xopenex HFA for rescue medication.
D. Educate on the use of albuterol nebulized
solution instead.
A. No. Genetic testing is not recommended in
patients that are on an appropriate treatment
regimen.
B. No. African Americans are advised against
genetic testing because they do not have genetic
polymorphisms implicated in asthma.
A. All children with asthma will have symptoms
into adulthood.
B. His chances are quite good because of the
eosinophils found in his blood and sputum.
New Therapies in Asthma
26
ACSAP 2013 • Pulmonary and Preventive Care
C. Yes. If identified, genetic markers may help
us distinguish why your medications are
inadequate.
D. Yes. Genetic testing may be useful to help
us determine if you can discontinue your
prednisone.
D. Prednisone 2.5 mg daily
Questions 9–12 pertain to the following case.
S.B.is a 43-year-old African American woman (height
5′4″, weight 143 lb) with severe persistent asthma, rheumatoid arthritis in her hands, allergic rhinitis, eczema,
gastroesophageal reflux disease, and type 2diabetes mellitus. Her current drugs are ciclesonide 160 mcg/puff
2 puffs twice daily, albuterol HFA 1 or 2 puffs every 4-6
hours as needed for wheezing/SOB, zafirlukast 20 mg
twice daily, methotrexate 20 mg weekly, folic acid 1 mg
daily, fluticasone 50 mcg/spray 2 sprays each nostril once
daily, mometasone cream 0.1% twice daily to affected skin,
metformin 1g twice daily, glipizide XL 10 mg once daily,
and aspirin 81 mg once daily. Examination shows her oxygen saturation at 90% on room air; her blood pressure is
134/84 mm Hg, and her heart rate is 94 beats/minute. Her
father died at age 74 after a myocardial infarction (MI),
and her mother has type 2 diabetes mellitus and rheumatoid arthritis. S.B.checks her peak flow rates routinely
and they typically are between 270–280 L/minute in the
morning. Her personal best is 350 L/minute. Laboratory
results are as follows: IgE level 524 U/mL (normal: 4.2595 U/mL); skin prick testing (+) feather mix, cat hair,
dog hair, rat epithelial (+) Bermuda grass, hickory/pecan
mix (+) Dermatophagoides farinae (dust mites). S.B.
hands you a prescription for salmeterol Diskus. “I want to
breathe better so I can keep up with my kids, but I’ve heard
this medicine is deadly. Should I be worried?”
Questions 6–8 pertain to the following case.
Q.T. is a 32-year-old woman with asthma. Her current
drugs include a medium-dose inhaled corticosteroid
(ICS) plus a long-acting β-agonist (LABA), a short-acting β-agonist (SABA) for rescue use, montelukast 10 mg
once daily, fexofenadine 180 mg once daily, and a prenatal
vitamin once daily. Q.T. still experiences daily wheezing, but she is still able to make it to the gym most days.
She states she wakes up with a “tight chest” and coughing about twice per week and uses her rescue medicine
at least 3 days per week. She checks her peak flow occasionally; she states it is typically in her yellow zone based
on a personal best she recorded 2 years ago. She recently
got married and is interested in family planning. She is
concerned about her asthma control if she becomes pregnant and has investigated genetic testing. Q.T. seeks your
advice regarding how to interpret the results of her “athome DNA” sample which reveal she is positive for the
16Arg/Arg polymorphism.
6. Which one of the following is the best education point
to give Q.T.?
A. Your rescue medication is appropriate given your
phenotype.
B. The effectiveness of your LABA may be less than
desirable
C. Montelukast may not provide added benefit for
your asthma.
D. LABAs are contraindicated for 16Arg/Arg
patients.
9. Which one of the following is the best response to
give S.B.?
A. Salmeterol is better avoided by African
Americans, so let me call your doctor to
recommend an alternative.
B. New evidence shows salmeterol can cause
problems, but this is likely OK because you are
taking another controller medicine.
C. New evidence shows salmeterol can cause
problems, but this is likely OK for you because
your asthma is controlled.
D. Salmeterol is fine for your asthma, but let me
recommend to your doctor a device that will be
easier for you to use.
7. Based on both her genetic findings and current symptoms, which of the following is the most appropriate
change to Q.T.’s current regimen?
A.
B.
C.
D.
Discontinue montelukast.
Add omalizumab.
High-dose ICS plus LABA.
Add prednisone daily.
10. S.B.returns 2 months later and reports some improvement in her asthma control. She states she is still
experiences a “runny nose and itchy, watery eyes”
nightly and has to always keep tissues on hand. She is
using her albuterol less (down to once per week) and
her asthma control test score is 19. Which one of the
following would provide the most benefit to S.B.?
8. Two months after starting her new regimen, Q.T.
is still experiencing symptoms and her asthma is
assessed as not well controlled. Which one of the following is best to recommend for Q.T.?
A. Bronchial thermoplasty.
B. Sputum induction test.
C. Fraction of exhaled nitric oxide (FeNO)
assessment.
ACSAP 2013 • Pulmonary and Preventive Care
A.Omalizumab.
B.Prednisone.
27
New Therapies in Asthma
C.Montelukast.
D.Famotidine.
B. An 18-year-old college freshman with irritable
bowel disease.
C. A 62-year-old retired man with osteoarthritis of
the knee.
D. A 24-year-old man with poorly controlled
bipolar disorder.
11.On the basis of her current signs and symptoms,
which one of the following emerging therapies for
asthma would have the most theoretical benefit for
S.B.?
15. A 13-year-old girl is accompanied by her mother for
a follow-up asthma appointment. The patient is difficult to communicate with as she rarely looks up
from her iPhone and is texting throughout the visit.
Her mother states the girl uses her iPhone regularly,
has an iPad at home, and uses the family desktop
computer for homework. She adds that her daughter is quite mature for her age and doesn’t like to be
treated like a small child. The mother states she lays
her medicine out for her daughter every morning and
evening but they are rarely “empty” when she gets
her monthly refill. The patient has had allergen skin
prick testing and knows her asthma triggers are dust,
tobacco smoke, and animal dander. The mother also
states that the girl has given up on the idea of trying
out for the school volleyball team this year because
of her problems with breathing. The patient’s medical history includes poorly controlled asthma, allergic
rhinitis, and attention deficit/hyperactivity disorder.
A chart review reveals the patient routinely shows
up for appointments, and her refill history shows
monthly fills. The girl demonstrates adequate device
technique with her metered-dose inhaler. Her current drugs are budesonide/formoterol metered-dose
inhaler 160/4.5 mcg 1 puff twice daily, desloratadine
10 mg once daily, methylphenidate 10 mg three times
daily, and albuterol HFA 1 or 2 puffs every 4-6 hours
as needed for wheezing or SOB.W hich one of the
following technological aids would be best to recommend for this patient?
A.Oligonucleotide.
B.Anti–TNF-α.
C. A chemoattractant receptor-homologous
molecule (CRTH2) antagonist.
D. A DP-receptor agonist.
12. Which one of the following nonpharmacologic techniques is best to recommend for S.B.?
A.
B.
C.
D.
Acupuncture treatments.
Mattress and pillow encasings.
A basement dehumidifier.
Elevate the head of her bed.
13. A 40-year-old man with asthma (height 5′9″, weight
283 lb) routinely participates as a research subject in
ongoing asthma trials. He states “I’m always looking
for the next best thing to make my asthma better. I
just want to sleep better and not have symptoms at
work that require me to take breaks and use my rescue
inhaler. I’d also like to cut down on visits to the ED.
I’m worried my boss is going to kick me off his insurance because I’ve had so many hospital stays!” The
patient’s medical history includes poorly controlled
asthma, eczema, migraine headaches, and obesity.
His current drugs are salmeterol/fluticasone 250/50
mcg 1 puff twice daily, prednisone 5 mg once daily,
sumatriptan 100 mg as needed for headaches, and
orlistat 60 mg twice daily. His vital signs are: blood
pressure 138/78 mm Hg, heart rate 74 beats/minute,
temperature 97.9°F, IgE concentration 100 U/mL
(normal 4.2–595 U/mL). His sputum induction test
shows (+) eosinophils (5%). Blood eosinophils are
(+): 600 cells/mL (normal < 350 cells/mL). Which
one of the following emerging therapies would be best
to recommend for this patient?
A.AsthmaSense.
B.abriIz.
C.Asthmapolis.
D. My Asthma Log.
16. A 39-year-old man (height 6′1″, weight 200 lb) is seen
for a follow-up asthma appointment. His medical history includes very poorly controlled asthma, erectile
dysfunction, degenerative disk disease, and hypertension. His current drugs include mometasone/
formoterol 200/5 mcg 2 puff twice daily, albuterol
HFA 1 or 2 puffs every 4–6 hours as needed for shortness of breath/wheezing, sildenafil 50 mg as needed,
naproxen 500 mg twice daily, hydrochlorothiazide
12.5 mg once daily, and calcium/vitamin D (500/500
mg) 1 tablet twice daily with meals. His vital signs
are oxygen saturation 97% on room air, blood pressure 130/74 mm Hg, heart rate 90 beats/minute, peak
A. A CRTH2 antagonist.
B.Oligonucleotide.
C.Anti-IL-5.
D. A TNF-α antagonist.
14. Four patients all have very poorly controlled asthma
on high dose ICS plus LABA. Which one of these
patients would theoretically benefit the most from a
trial of CNTO-148 (golimumab)?
A. A 50-year-old architect with severe plaque
psoriasis.
New Therapies in Asthma
28
ACSAP 2013 • Pulmonary and Preventive Care
expiratory flow 300 L/minute (best of three with adequate effort, personal best 550 L/minute). His social
history is positive for tobacco use (one-half pack per
day), and he states that he doesn’t drink alcohol or
take illicit drugs. An induced sputum sample predominant WBC found: neutrophils. Other test results
are: FeNO 8 parts/billion and IgE 250 U/L (normal
range, 4–595 U/L). Skin prick testing: (-) grasses,
trees, and animal allergens. Four months ago, his pulmonary function test results were as follows:
Test
Pre-bronchodilator
Post-bronchodilator
FEV1
72
80
FEV1/FVC
59
82
FVC
73
79
allergic rhinitis, and osteopenia. Her current drugs are
fluticasone/salmeterol diskus 500/50 mcg 1 puff twice
daily, prednisone 2.5 mg once daily, albuterol HFA 1
or 2 puffs every 4–6 hours as needed for shortness of
breath, levocetirizine 5 mg once daily, alendronate 35
mg once weekly, calcium/vitamin D twice daily, and
omalizumab injections once monthly. She was started
on tiotropium 18 mcg once daily 3 months ago, and
pharmacy claims data reveal she is adherent to all medications. She uses her rescue inhaler several times per
day, wakes up wheezing 4 or 5 times per week, and is
no longer able to participate in her select volleyball
team because of symptoms. Her Asthma Control Test
score is 8. Her vital signs are blood pressure 110/62
mm Hg and heart rate 70 beats/minute. Her genotype
is Arg16/Gly. A sputum sample shows predominant
eosinophils. Other test results are FeNO 54 parts/billion, IgE 50 u/L, and skin prick testing (+) ragweed,
pigweed, cat hair, feather mix, (+) Alternaria alternata.
Which of the following is best to recommend for this
patient?
Which one of the following would be best to add to
his regimen?
A. Tiotropium Handihaler 18 mcg once daily.
B. Montelukast 10 mg once daily at bedtime.
C. Mometasone/formoterol 200/5 mcg 4 puffs
twice daily.
D. Omalizumab 300 mg subcutaneously injected
every 2 weeks.
A. Increase omalizumab to twice monthly
injections and prednisone to 5 mg daily.
B. Discontinue tiotropium and add montelukast 10
mg once daily.
C. Continue tiotropium and schedule her for
bronchial thermoplasty.
D. Switch albuterol to ipratropium as her rescue
medication and discontinue prednisone.
17. A 45-year-old African American woman (height 5′7″,
weight 180 lb) has a medical history that includes
persistent asthma, allergic rhinitis, polycystic ovary
syndrome, and type 2 diabetes mellitus. Her current drugs are fluticasone HFA 220 1 puff twice daily,
prednisone 5 mg once daily, metformin 500 mg twice
daily, and albuterol HFA 1 or 2 puffs every 4–6 hours
as needed for shortness of breath. She uses her rescue
inhaler several times per day, wakes up coughing and
wheezing 5–6 times per week, and can no longer participate in her weekly yoga class. The patient’s Asthma
Control Test score is 10. Her vital signs include blood
pressure 100/82 mm Hg and heart rate 80 beats/
minute. Her genotype is 27Glu/Glu. A sputum test
shows predominant eosinophils. Other test results
are FeNO 4 parts/billion and IgE 100 U/L. Skin prick
testing results are: (-) ragweed, pigweed, (-) ladybug,
cat hair, feather mix, (-) Alternaria alternata.
19.A 52-year-old man (height 5′9″, weight 190 lb) is
following up on his asthma drug regimen. He was
told to make the appointment because of his “out
of control” asthma. He states he isn’t able to attend
bowling league, often uses his rescue medicine both
at home and at work, and is having frequent nighttime symptoms and awakenings. The patient works as
a technician for a spray-on truck bed liner company.
His medical history includes asthma and carpal tunnel syndrome.
Which one of the following is most appropriate to recommend for this patient?
A. Continue current drug regimen.
B. Add tiotropium 18 mcg once daily.
C. Increase prednisone to 10 mg by mouth once
daily.
D. Fluticasone/salmeterol HFA 230/21 2 puffs
twice daily.
Drug
Fluticasone/
salmeterol
500/50 1 puff
twice daily
18 A 36-year-old woman (height 5′4″, weight 102 lb)
has a medical history that includes persistent asthma,
ACSAP 2013 • Pulmonary and Preventive Care
His medications and refill record are summarized in
the table below.
29
Fill dates
Refills
Notes
remaining
January 1 5
April: Pt
February 1 4
demonstrated
March 1
3
adequate Diskus
April 2
2
technique. At next
May 1
1
follow-up assess
June 2
0
inspiratory rate and
breath-holding.
New Therapies in Asthma
Ventolin HFA
1-2 puffs every
4-6 hours as
needed for
SOB/ wheeze
January 10
March 1
April 15
May 20
June 30
Acetaminophen June 2
325 mg /
hydrocodone
10 mg
1 tablet at
bedtime as
needed for pain
#30
5
4
3
2
1
January: Pt
demonstrated
adequate metereddose inhaler
technique with
spacer
Reviewed proper
cleaning of spacer
0
Further asthma studies show his genotype is 16Arg/
Arg. He was not able to produce an adequate sample
for sputum testing, and his FeNO sample was contaminated with nasal NO. IgE test results are 405 U/L.
Skin prick testing: (-) American elm, ragweed, Russian
thistle, cockroach mix, and Dermatophagoides farina.
His vital signs are blood pressure 108/90 mm Hg and
heart rate 82 beat/minute. His PEF is 410 L/minute
(personal best 500 L/minute). Which one of the following is most appropriate for this patient?
A. Fluticasone/salmeterol 250/50 1 puff twice daily
plus tiotropium 18 mcg once daily.
B. Fluticasone/salmeterol 500/50 1 puff twice daily
plus mometasone 200 mcg once daily.
C. Fluticasone/salmeterol 500/50 1 puff twice daily
plus theophylline SR 100 mg twice daily.
D. Fluticasone/salmeterol 250/50 1 puff twice daily
plus omalizumab 375 mg every 2 weeks.
20.Two hundred patients are enrolled in a trial to
determine the effect of tiotropium added to highdose ICS plus LABA on FEV1. One-half of these
patients received high-dose ICS plus LABA (control arm) and one-half received high-dose ICS plus
LABA plus tiotropium (experimental arm). Results
reveal patients in the experimental arm had an FEV1
improvement of 15% over the control arm group of
5%. Which one of the following represents the number of patients needed to treat with tiotropium for 1
patient to show improvement in FEV1?
A.1.
B.10.
C.100.
D.1000.
New Therapies in Asthma
30
ACSAP 2013 • Pulmonary and Preventive Care
Learner Chapter Evaluation: New Therapies in Asthma.
As you take the posttest for this chapter, also evaluate the
material’s quality and usefulness, as well as the achievement
of learning objectives. Rate each item using this 5-point
scale:
•
•
•
•
•
Use the 5-point scale to indicate whether this chapter prepared you to accomplish the following learning objectives:
12. Evaluate interventions based on the etiologies, status,
and control of asthma.
13. Develop and justify optimal therapeutic regimens
based on the underlying pathophysiology of asthma
and current evidence.
14. Devise an asthma education care plan for a patient or
family member(s).
15. Demonstrate an understanding of pharmacogenomic
testing and how results influence treatment decisions in
patients with asthma
16. Demonstrate an understanding of emerging therapies
in the treatment of asthma and judge when they would
be applicable in patient care
17. Display insight into technological advances in
asthma care and recommend them to patients when
appropriate.
18. Please expand upon any of your above responses, and/
or provide any additional comments regarding this
chapter:
Strongly agree
Agree
Neutral
Disagree
Strongly disagree
1. 2. 3. 4. The content of the chapter met my educational needs.
The content of the chapter satisfied my expectations.
The author presented the chapter content effectively.
The content of the chapter was relevant to my practice
and presented at the appropriate depth and scope.
5. The content of the chapter was objective and balanced.
6. The content of the chapter was free of commercial bias.
7. The content of the chapter was useful to me.
8. The teaching and learning methods used in the chapter
were effective.
9. The active learning methods used in the chapter were
effective.
10. The learning assessment activities used in the chapter
were effective.
11. The chapter was effective overall.
ACSAP 2013 • Pulmonary and Preventive Care
31
New Therapies in Asthma